FRAUNHOFER INSTITUTE FOR MOLECULAR BIOLOGY AND APPLIED ECOLOGY IME

Years

ANNUAL REPORT 2019 60 YEARS OF RESEARCH FOR TODAY, TO- MORROW AND THE DAY AFTER TOMORROW Welcome The Institute Our Research In Dialog In Focus Selected P e o p l e a n d E v e n t s Facts 2019 Publications E d i t o r i a l n o t e s

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60 years of history The radiokitchen – Quo Biological plant protection: Understanding flower Plant cell packs named Brief reports Publications vadis, molecule? With microbes against development - Targeted cookies Employees, meetings, Fraunhofer IME profile insect pests increase of plant biomass! ­suc­cesses and new per­ Patents Colorful potato PD Dr. Gundula Noll Characterization of spectives at Fraunhofer IME Fraunhofer IME within the An interview with ­protein interactions in Bachelor’s, Master’s, Fraunhofer-Gesellschaft Translation of research Dr. Kwang-Zin Lee living cells State Examination into medical applications and Doctoral Theses Advisory Board Deciphering the mecha- Insect virulence inhibitors nisms of rubber biosyn- Networks in science Business fields/areas for the therapy of lung thesis in dandelions and industry Molecular Biotechnology, infections Applied Ecology and Bio­ Impact of insect meal on Photo acknowledgments

resources, Recycling CO2 emissions fat metabolism Translational Medicine with bacteria Editorial notes Novel insights into the Institute management and Using artificial intelligence mechanism of caspase-6 locations to predict biological age Bioconcentration ­studies Institute data with the crustacean ­Hyalella azteca 60 YEARS: TEMPORA MUTANTUR, NOS ET MUTAMUR IN ILLIS

70 years of the Fraunhofer-Gesellschaft, 60 years of Fraunhofer at Schmallenberg, two digitization for sustainable (bio)production. A further highlight is the market launch of a bicycle good reasons to celebrate. On December 1, 1959, the Fraunhofer-Gesellschaft integrated tire made from latex of the Russian dandelion - the optimization of the plant and the process the research­ laboratory founded two years earlier by Dr. Karl Bisa in Schmallenberg into the for extracting the valuable material were established at Fraunhofer IME in Münster. ­Fraunhofer Institute for Aerobiology IAe. In cooperation with other Fraunhofer Institutes, the Translational Medicine division located in In 2019, the division “Applied Ecology and Bioresources” celebrated the 60th anniversary Frankfurt am Main and Hamburg fosters medical progress through transdisciplinary cutting-­ of the founding of the Fraunhofer site Schmallenberg. Initially with a focus on inhalation edge research. The so-called 4D concept plays a significant role in this regard. In order to ­toxicology, it can be regarded as the origin of Fraunhofer health research. As the ­Institute for ­optimally address the 4D (“Drugs”, “Diagnostics”, “Data”, “Devices”) to the benefit of the toxicology and aerosol research ITA moved to Hannover in 1985 (today Fraunhofer ITEM), patient, experts from various scientific disciplines (physicians, natural scientists, computer in ­Schmallenberg ­environmental risk assessment of substances became the dominant ­issue scientists, engineers) need to work together. Based on the diversity of its constituent institutes, ­(Institute for ­Environmental Chemistry and Ecotoxicology IUCT). Today, the branch of ­Applied Fraunhofer is the only research organization that, is able to optimally apply all 4D in health Ecology holds a leading position in Europe regarding research for and development of research and thus constitutes the ideal partner for innovative development projects. Artificial ­substance-related test methods (OECD, EU, DIN/ISO), test strategies and evaluation concepts intelligence and machine learning methods are increasingly being employed, for example, in for environmental risk and consumer exposure assessment. It is acknowledged as scientific the development of a digital twin in the Fraunhofer lighthouse project MED²ICIN together mediator between regulatory authorities and industry. Our success is reflected by the steady with an algorithm for testing biological age. In the course of expansion of a biobank, a growth in business volume and staff. Both were doubled in the last 11 years at routinely high ­strategic ­cooperation in the field of spondyloarthritides has been established with the German industry yields of more than 50 percent, triggering the current construction of new laboratory ­Rheumatism Research Center Berlin. Fraunhofer IME is also the strategic research partner of a capacities and meeting rooms. US biotech company for the development of a drug for a rare disease. Our efforts to ­establish The branch Bioresources, funded by the LOEWE programme in Gießen, developed to ­become an inflammation clinic as an integrative concept for the effective treatment of immune-­ the leading research centre for insect biotechnology and will move into its new building in mediated diseases is of major importance. The aim is to connect excellent transdisciplinary 2020. A core business is the valorization of biodiversity as a resource for the bioeconomy. research with interdisciplinary care, in an innovative and cost intelligent way, for the well-being ­Example ­platforms are the microbial strain collection taken over from Sanofi and a library of of patients and to contribute to the development of sustainable healthcare in Germany. animal toxins. The division Bioresources develops innovative technologies for the sustainable ­control of detrimental­ and vector insects, for the industrial use of insects (insect farming) and Finally, we wish to thank all those who, through their continued commitment and support, the conservation­ of biodiversity. have contributed to our success in 2019. We are most grateful to our business and research partners for their excellent and dependable cooperation, and to our staff for their dedication. The “Molecular Biotechnology“ division was established 20 years ago and has further We wish ­everyone involved an equally successful year in 2020, stay healthy! ­expanded its activities in white and green biotechnology. Together with industrial partners, a number of bio-economic processes and products have been transferred to commercial Frankfurt am Main, Schmallenberg and Aachen in March 2020 ­application, such as plant stem cells for the cosmetics industry, a cell-free expression system, an amylose-free potato variety and tires with natural rubber from alternative plant sources. A further focus at the ­Aachen location is the utilization of anaerobic bacteria to produce ­various alcohols and jet fuel from off-gases from the steel industry. Another focus is the High ­Performance Center “Networked, Adaptive­ Production“ which has the aim to enable a much more flexible and efficient design of demanding value-added chains for the manufacture of Prof. Dr. Dr. Gerd Geißlinger Prof. Dr. Christoph Schäfers Prof. Dr. Stefan Schillberg technical and biological products. After three ­successful years, the three Fraunhofer Institutes IME, ILT and IPT in Aachen were granted a project extension of initially one more year with a planned ­consolidation from 2021 onwards, in order to exploit the opportunities offered by

4 5 »1«

60 years ago, the research laboratory at the Schmallen- berg location was inte­ grated into the Fraunhofer-­ Gesellschaft.

7 GESCHICHTE AUS 60 JAHREN

60 YEARS OF HISTORY 2006 The division Molecular Biology moves into its own new 2015 Prof. Prüfer and Dr. Schulze Gronover, both ­Fraunhofer building near the RWTH Aachen University. IME, together with Dr. Recker from Continental Reifen Deutschland GmbH are awarded the Joseph von Fraunhofer The foundation of the Fraunhofer-Gesellschaft on March 1985 The Schmallenberg and Hanover locations are split 2008 The Fraunhofer Food Chain Management Alliance is Prize for their research on the Russian dandelion and the 26, 1949 laid the groundwork for the leading organization into two independent Fraunhofer Institutes. Renaming the founded. Under the leadership of the Fraunhofer IME division­ development of its application. in the field of applied research and development in Europe. ­Schmallenberg location Fraunhofer Institute for Environmental­ “Applied Ecology“, several Fraunhofer Institutes are working ­Fraunhofer IME is one of the first ten Fraunhofer Institutes. Chemistry and Ecotoxicology IUCT reflects the institute's new jointly to improve food safety. 2017 Prof. Fischer leaves Fraunhofer IME and hands over the research priorities. acting management to the head of the locations in Frankfurt 1959 On December 1, a research laboratory set up by Dr. 2009 A new Fraunhofer IME project group “Bioresources“ am Main, Schmallenberg und Aachen: Prof. Geißlinger, Prof. Bisa in Schmallenberg is integrated into the Fraunhofer-­ 1992 The Central Institute of Nutrition of the former Academy headed by Prof. Vilcinskas is established at the Justus Liebig Schäfers and Prof. Schillberg. Prof. Geißlinger is executive Gesellschaft named Fraunhofer Institute for Aerobiology IAe. of Sciences of the German Democratic Republic (GDR) is the University Gießen (JLU). In the following years insect biotech- director of Fraunhofer IME as well as Health Research Officer Construction of the main building begins in the same year. origin of the Fraunhofer IUCT branch “Department Biochem­i­ nology is established at the JLU and Fraunhofer. The location of the Fraunhofer-Gesellschaft. The institute is restructured cal Ecotoxicology“ in Potsdam. It is closed seven years later. in Gießen is appointed as a LOEWE Center (Hessen State into three divisions: Molecular Biotechnology, Translational 1969 The institute has now about 70 employees and is direc- Offensive for Development of Scientific-Economic Excellence). Medicine, Applied Ecology and Bioresources. ted by Dr. Oldiges, Dr. Rüterjans and Prof. Stöber. The research 1998 To strengthen the biotechnological competence of the focus lies on protecting people from air pollutants. Until 1971, Fraunhofer-Gesellschaft, the new department “Molecular 2010 In cooperation with Prof. Prüfer's Department of 2018 Fraunhofer IME, together with the other core institutes it is financed mainly by the Federal Ministry of Defence. Biotechnology“ is founded at Fraunhofer IUCT under the Plant Biotechnology, the Fraunhofer IME branch lab “Plant IZI and ITEM, establishes the Fraunhofer Cluster of ­Excellence direction of Dr. Fischer. ­Bio­polymers“ is launched at the University of Münster (WWU). for Immune-Mediated Diseases CIMD. The central aim is the 1972 The German Federal Ministry for Research and Techno- Prof. Klein was awarded the Order of Merit of the Federal translation of innovative ideas and identified targets into logy takes over the institutional support of the Fraunhofer-­ Republic of Germany for his achievements in ecological 2011 Prof. Schillberg, Dr. Rademacher and Dr. Drossard were individualized therapies for immune diseases. Fraunhofer IME Gesellschaft. At Fraunhofer IAe, research questions of general ­chemistry. awarded the Fraunhofer Prize Human-Centered Technology is instrumental in the conception of the PoC initiative of Helm- environmental protection become more prominent. for the development of a production platform for plant-based holtz-Fraunhofer-German university medicine and receives one 2000 The Federal Environmental Specimen Bank is being biopharmaceuticals. of four funded projects in the pilot phase. The institute is also 1979 The institute is renamed to Fraunhofer Institute for set up at Fraunhofer IUCT in Schmallenberg as a long-term involved in the MED²ICIN Fraunhofer lighthouse project. ­Toxicology and Aerosol Research ITA and an additional location­ ­archive for documenting the state of the environment in 2012 The new Fraunhofer Project Group “Translational Medici- is added. The research focus “Human Health“ under the Germany. ne and Pharmacology“ starts its work at the Goethe­ ­University 2019 Our sixtieth year is marked by construction projects: In ­direction of Prof. Stöber is the focus of toxicological research Dr. Fischer is appointed Chair of Molecular Biotechnology­ at Frankfurt am Main with the help of LOEWE funding from Gießen, the Bioresources branch will move into its new institu- in Hanover. Dr. Oldiges is in charge of research at Schmallen- the RWTH Aachen University. the state of Hessen. Under the direction of Prof. ­Geißlinger, te building, Translational Medicine is planning a new institute berg focusing on the protection of the environment. a ­LOEWE Center is being established in the ­following years, building in Frankfurt am Main and in Schmallenberg, extensive 2001 At the end of September Prof. Klein took his retirement. ­bringing together drug research, preclinical and clinical model conversion and new building measures are in full swing. 1982 Dr. Hochrainer, Dr. Oberdörster and their team were Prof. Fischer is appointed the new head of the institute. Dr. development, and clinical research. awarded the Joseph von Fraunhofer Prize for their research on Schillberg receives the Joseph von ­Fraunhofer Special Prize for Fraunhofer IME has written its own history over the past the carcinogenicity of cadmium aerosols. his research work on molecular farming. Due to the successful 2014 With the integration of the European ScreeningPort 60 years - and it is far from over. With the spirit of scientific work in the department of Molecular Biology, the institute GmbH in Hamburg into Fraunhofer IME, the institute is further ­inquiry to guide us, we invent the shape of things to come 1983 Prof. Klein is appointed head at the Schmallenberg is renamed to Fraunhofer Institute for Molecular Biology and expanding its strength in pharmaceutical drug ­research. The – the world of tomorrow and beyond. The future has always branch of the institute, initially together with Dr. Oldiges. Applied Ecology IME. Fraunhofer IME is a founding member of work of the cooperation project on natural rubber from been our driving force for the development of sustainable The fate of chemicals in the environment and their effects on the Fraunhofer Group for Life Sciences, a body strengthening ­Russian dandelion is rewarded with the ­GreenTec Award. solutions at the service of people and the environment. environmental organisms is now the focus of research. the role of the biosciences within the Fraunhofer-Gesellschaft.

8 9 A AE MB BR TM

FRAUNHOFER IME PROFILE Molecular Biotechnology Applied Ecology and Translational Medicine Bioresources

Since the beginning of 2017, Fraunhofer IME has comprised the three divisions of Molecular Molecular Biotechnology is the basis of We develop experimental and model-­ Translational Medicine contributes Biotechnology, Applied Ecology and Bioresources, and Translational Medicine. On July 1, 2018, a modern bioeconomy and contributes based methods for the assessment of steadily and substantially to the develop- the Executive Board of the Fraunhofer-Gesellschaft appointed Prof. Dr. Dr. Gerd Geißlinger sustainably to the knowledge-based risks to ecosystems posed by potentially ment of new approaches for the diag- as the Executive Director of Fraunhofer IME. He had been Acting Executive Director since production and industrial use of renew­ hazardous substances, as well as for the nosis and treatment of diseases that are ­January 2017. Prof. Dr. Schillberg and Prof. Dr. Schäfers are acting members of the institute able raw materials. On behalf of our analysis of consumer exposure to such inadequately understood or con­trolled. ­management. customers, the Molecular Biotechnology substances within the environment. We The field of translational medicine spans Division develops tailored plants, animal often act as scientific mediators between the value chain, from target identifi- Fraunhofer IME is a strong partner for contract research in the areas of pharmaceuticals, cells and microbes for applications such commercial producers and the regula- cation through active agent screening medicine, chemicals, bioeconomy and agriculture, as well as environmental and consumer as the production of food and renew­ tory authorities. Another focal point of and translational preclinical validation ­protection. Our research and development portfolio focuses on industry, small and medium able raw materials, the manufacture of our work is the identification of active to clinical trials. One research focus enterprises and on the public sector. In 2019, Fraunhofer IME collaborated with more than 100 technical and pharmaceutical proteins, substances from bioresources such as is the repositioning of known active national and international industrial clients and several international industrial associations, for and the handling of anthropogenic plants, microbes and insects, plus the agents ­within the disease areas of pain, whom confidential projects were conducted. pollutants including greenhouse gases, development of concepts for the sus- rheuma­toid arthritis, sepsis, multiple which we can exploit to produce valu­ tainable agricultural production of active sclerosis and inflammation. We offer a Our interdisciplinary organization allows us to process complex projects across departments and able ­substances. In recent years, we substances from plants. We also develop specialized spectrum of disease models where appropriate, also focuses on cooperation with external institutes and partners. We work have established ourselves successfully biological and biotechnological methods as well as highly sensitive analysis, bio­ closely with basic research and are internationally networked. Our laboratories with state-of- in the research landscape and on the for the control of pest and vector insects i­nformatics and biomarker platforms. the-art equipment and complex environmental simulation facilities allow us to offer a wide market due to our synergistic activities in and utilize insects to generate protein Our clinical trials follow quality-by-­ range of research and services as well as studies according to good laboratory practice (GLP). the fields of green and white biotechnol­ from organic waste. design standards to reduce attrition ogy. We offer our partners in academia, rates and generate as much scientifically At the end of 2019, the institute employed 533 personnel working at the Aachen, Münster, industry and the regulatory authorities relevant information as possible. Schmallenberg, Gießen, Frankfurt am Main and Hamburg locations. We have close ties with a comprehensive research and service the Department of Biology and Biotechnology of Plants at the University of Münster, the portfolio. Institute for Clinical Pharmacology at the Goethe University Frankfurt, Frankfurt am Main, the Department of Applied Entomology at the Justus-Liebig University Gießen, and the world’s first Institute for Insect Biotechnology, founded in Gießen in 2016. eW cooperate with many international research partners and remain in close contact with universities and other re­search organizations. Our aim is to recog­nize trends and developments as they emerge, and to de- velop and implement novel research strategies and technologies. Symbols used in the annual report

AE MB Division BR Division TM Division Molecular Biotechnology Applied Ecology and Bioresources Translational Medicine

10 11 FRAUNHOFER IME WITHIN THE ADVISORY BOARD ­FRAUNHOFER-GESELLSCHAFT

Founded 70 years ago, the Fraunhofer-Gesellschaft is the Fraunhofer Clusters of Excellence promote the cooperative Advisory Board members advise the Fraunhofer-Gesellschaft as well as the individual institutes and promote their connection to ­world’s leading applied research organization. With its development and processing of system-relevant topics through partners from industry, science and the public sector. focus on developing key technologies that are vital for the an inter-institute research structure in a “virtual institute“. future and enabling the commercial exploitation of this Fraunhofer IME is one of the three core institutes of the Fraun- In 2019, the following representatives from government, industry and academia were members of the Fraunhofer IME Advisory work by ­business and industry, Fraunhofer plays a central hofer Cluster of Excellence for Immune-Mediated Diseases Board: role in the innovation process. As a pioneer and catalyst CIMD. Dr. Harald Seulberger (Chairman) Prof. Dr. Ulrich Rüdiger for groundbreaking developments and scientific excellence, www.cimd.fraunhofer.de/en.html BASF SE, Limburgerhof Rector of RWTH Aachen University, Aachen (guest) Fraunhofer helps shape society now and in the future. The Fraunhofer-Gesellschaft­ currently operates 74 institutes and High Performance Centers organize the collaboration Dr. Carl Bulich Dr. Karin Schlesier research ­institutions ­throughout Germany. The majority of ­between university and non-university research with ­industry. German Plant Breeders’ Association, Bonn German Federal Institute for Risk Assessment, Berlin the ­organization’s 28,000 employees are qualified scientists ­Universities, higher education institutions, Fraunhofer and engineers, who work with an annual research budget of ­Institutes and further non-university research institutions work Dr. Friedrich Dechet Prof. Dr. Angelika Vollmar 2.8 billion euros. Of this sum, 2.3 billion euros is generated together at one location on specific topics in order to quickly Industrial Association Agrar, Frankfurt am Main Ludwig-Maximilians-Universität München, München through contract research. transfer innovations to application. Fraunhofer IME in Aachen The Fraunhofer Institutes are organized in eight thematically is involved in the “Networked, adaptive production“ High Prof. Dr. Adolf Eisenträger Prof. Dr. Johannes Wessels oriented alliances. Their goals are the technical coordination Performance Center. German Federal Environment Agency, Dessau-Roßlau Rector of the University of Münster, Münster (guest) within the Fraunhofer-Gesellschaft, the bundling of core com- www.vernetzte-adaptive-produktion.de/en.html petencies and a joint appearance on the market. Fraunhofer Stefan Lütke Entrup Dr. Hans-Ulrich Wiese IME is a member of the Life Sciences Network, a scientific-­ Fraunhofer lighthouse projects put the focus on strategic Gemeinschaft zur Förderung von Pflanzeninnovation e. V., Formerly member of the Executive Board of Fraunhofer technological community of highly qualified experts from key objectives with a view to developing practical solutions from Bonn (permanent guest) areas of modern life sciences from six Fraunhofer Institutes which economies such as Germany’s can benefit. The projects and one Fraunhofer Research Institution. aim to turn original scientific ideas into marketable products as Prof. Dr. Heyo Kroemer (Deputy Chairman) Prof. Dr. Birgitta Wolff www.lifesciences.fraunhofer.de/en.html quickly as possible. Fraunhofer IME is contributing its expertise University of Göttingen, Göttingen President of the Goethe University Frankfurt, Frankfurt am to the lead project MED²ICIN. Main (guest) Institutes or departments of institutes with different compe- https://websites.fraunhofer.de/med2icin/ Prof. Dr. Joybrato Mukherjee tencies cooperate in Fraunhofer alliances to jointly develop President of the University of Gießen, Gießen (guest) and market a business segment. The Fraunhofer Alliances The Fraunhofer Sustainability Network is an initiative of 20 The annual meeting of the Advisory Board was held on May make it easier for customers to access the results and services Fraunhofer Institutes aiming to raise awareness within the Ministerialrätin Andrea Noske 16, 2019 at Fraunhofer IME in Schmallenberg. The Executive of the Fraunhofer-Gesellschaft. Fraunhofer IME is involved in Fraunhofer Gesellschaft for the integration of sustainability Federal Ministry of Education and Research, Berlin Board of the Fraunhofer-Gesellschaft was represented by Dr. two alliances: issues. Johannes Landes, Director R&D-Contracts IPR. Fraunhofer Big Data and Artificial Intelligence Alliance: www.fraunhofer.de/en/about-fraunhofer/corporate-­ Dr. Dr. Christian Patermann www.bigdata.fraunhofer.de/en.html responsibility/governance/sustainability/fraunhofer-­ Formerly Director Directorate General for Research and Food Chain Management: www.fcm.fraunhofer.de/en.html sustainability-network.html Innovation of the European Commission, Bonn

12 13 BUSINESS FIELDS MOLECULAR ­BIOTECHNOLOGY

Bioproduction and Agroscience for Food Production of Recombinant Industrial Biotechnology and Feed Proteins

The business field Bioproduction and The business field Agroscience for Fraunhofer IME offers expertise in all Industrial Biotechnology focuses on the Food and Feed covers the ­agricultur­al ­aspects of the design, production, identification, sustainable ­production, value chain “from farm to fork“ and purification and characterization of processing and optimization of high- focuses on the development and recombinant proteins, including process value natural compounds, including improvement of plant traits, crops and development and scale-up from a chem­ical building blocks, bio based enabling technologies to increase the ­laboratory process to the manufacture fuels, fine chemicals, biomaterials and biomass of crops, the quality and yield of kilograms of clinical material under proteins for industrial applications of agricultural products, the ability of GMP conditions. Different systems and consumer products. This can be plants to grow in diverse environments, are ­available for the production of ­produced using a diverse array of and to withstand pests and diseases. specific protein products, involving ­organ­isms, from microorganisms and These traits are developed using both ­microorganisms, plant cells, animal cells plant cells through to animal cells. genetic modification (GM) and non-GM and whole plants as well as cell-free Here the value chain is covered: From ­approaches, and key technologies such expression systems. There has been target discovery and screening, the as genome editing and TILLING. a recent increase in the demand for development and optimization of The departments and project groups recombinant proteins produced at the production strains and the transfer of involved in this business field focus on kilogram scale for the pharmaceutical, laboratory-scale processes to scale up precision breeding techniques and the agriculture and cosmetic sectors, and for and pilot-scale manufacturing for future development and testing of GM crops. technological applications. In addition, industrial production and downstream Based on this wide-ranging expertise, the institute has its own new protein processes, including the evaluation of Fraunhofer IME acts as a preferred candidates in the pipeline, particularly MB economic feasibility. ­partner for academic laboratories, SMEs technical enzymes, foodstuff proteins, Prof. Dr. Stefan Schillberg Fraunhofer IME provides comprehen- and major agribusiness companies. diagnostic reagents and therapeutic [email protected] sive expertise in the development of proteins. innovative biotechnol­ogy platforms and optimized processes. The departments and project groups involved cover a range of different product types, from bulk chemicals and fuels such as isopropanol, isoprene and hexanol, Molecular Biotechnology: through to plant-based metabolites and Research, Development polymers such as rubber, inulin, cellulose and Services MB and industrial starches, and high-value Prof. Dr. Dirk Prüfer fine chemicals, proteins and industrial www.ime.fraunhofer.de/en/MB/RDS [email protected] enzymes.

14 15 BUSINESS FIELDS APPLIED ECOLOGY AND BIORESOURCES

Environmental Risk Food Safety and Quality Sustainable Agricultural Pro- Bioresources for the Insect Biotechnology

Assessment of Substances ­duction of Substances 4C24C Bioeconomy

We use our expertise in environmental The safety and quality of food depend We develop across divisions concepts for We use groups of organisms with great The development and application of analysis, experimental environmental on the production method and on the the sustainable agricultural production biodiversity as bioresources, including insect biotechnology allows us to use chemistry and ecotoxicology, and mod­ primary and further processing of agri- of substances for a diversified bioecon­ insects, bacteria and fungi. We combine insects, insect-derived molecules, cells or eling the bioaccumulation and effects cultural raw materials. We focus on the omy: Connecting niches to Chains of innovative technologies and established organs, and insect-associated microbes of substances, to assess the risks such qualitative properties of raw materials bioeconomic value added for Circular platforms to isolate and characterize as products or systems for diverse appli- substances pose to the environment. We and foods, and the damage caused by flow in a Climax economy. To achieve natural substances, and to evaluate their cations in medicine, industrial biotech- liaise with the regulatory authorities to harmful substances. For example, we this, amongst other things, we use potential for use in medicine, plant pro- nology, and the food and feed industry. formulate critical questions and draw take existing methods used to analyze Fraunhofer technologies of the lead tection and industrial biotechnology. In We also exploit insect cells as protein up test guidelines to address these risks. the metabolism of plant protection project Cognitive Agriculture to meet this way, novel molecules are identified expression systems and insect antennae On behalf of our partners in industry, products in crops and farm animals and socio-economic and ecological require­ to develop as antibiotics or ingredients as biosensors for drugs and explosives. we perform and evaluate complex adapt them to study the metabolism ments (Community claims) with new for the food and feed industry, such Furthermore, we develop insect models experimental and model-based studies of veterinary pharmaceuticals and feed Crops and changed livestock husbandry as flavoring agents, preservatives and for toxicology studies and use bio- to the highest scientific standards. We supplements, and we develop cell-based (Cattle/livestock). We take into account enzymes, leading to novel applications technology to control pest and vector use the analysis and classification of alternatives to animal testing. We track differentiated soil and microclimate and value chains. The Fraunhofer Evotec insects, for example RNA interference molecular mechanisms as screening breakdown and conversion products properties, the use and optimization of Natural Products Excellence Center for and the sterile insect technique. We also tools to assess the environmental impact by radioactive labeling throughout the plants for the production of valuable Infectious Diseases (FENPEC ID) with use insects for the conversion of organic of candidate products. We manage the food production cycle. As part of the and active substances (Aachen and the world's largest industrial Sanofi waste into proteins and fats for the food national Environmental Specimen Bank ­Fraunhofer Food Chain Management Münster), and waste and insects for strain collection of microorganisms is and feed industry. and perform environmental monitoring Alliance, we are developing rapid obtaining protein (Gießen). Regulatory also ­available for projects with other projects to identify potential environ- analytical techniques to monitor the requirements arising from digital agricul- ­industrial partners from non-competing mental pollutants and check prospective food chain. Aroma research combined ture in the application of plant protec- fields of application. assessments. with geographical information systems tion products, veterinary medicines and has highlighted links between cultiva- fertilizers, are also taken into account tion conditions and the quality of raw (Schmallenberg). foodstuffs.

Applied Ecology and ­Bio­resources: Research, ­Development and Services AE AE AE AE AE BR BR BR BR BR Dr. Dieter Hennecke Prof. Dr. Mark Bücking Prof. Dr. Christoph Schäfers Prof. Dr. Andreas Vilcinskas Prof. Dr.-Ing. Peter Czermak www.ime.fraunhofer.de/en/AEBR/RDS [email protected] [email protected] [email protected] [email protected] [email protected]

16 17 BUSINESS FIELDS TRANSLATIONAL MEDICINE

Assay Platforms and Drug Translational Compound Digital Health Research Clinical Research Discovery Validation

Our expertise is in modern drug dis- The business field Translational Com- We contribute to the digitalization of Clinical research is the decisive step in covery, enabled by our high ­quality pound Validation aims to develop the pharmaceutical research by estab- the development of new discoveries screening collections totalling over differ­entiated translational disease lishing the Fraunhofer “Medical Data in the life sciences for use in humans. 350,000 lead-like compounds, state models, measurement techniques, Space”, a decentralized data manage- We offer our customers the ­essential of the art automated infrastructure technologies and imaging procedures ment system for the autonomous and elements needed for successful ­clinical and well-established in-house in silico for early assessment of the efficacy and secure storage and exchange of medical trials, including the definition of screening platforms. This allows our safety of active compounds. In addition data between networked databases. ­appropriate scientific hypotheses and partners to realise their projects from to cell-based and cell-free systems, we For several pan-European projects we the patient groups and subgroups to be target validation through to preclinical also conduct experiments on rodents. provide our expertise in bioinformatics treated, combined with an individual, studies. We have established an exten- Our range of models is far wider than by implementing a Data Scientist to adaptive study design, employing the sive portfolio of target, phenotypic and the standard spectrum offered by ensure the highest standards in FAIR latest statistical and biomedical ­analysis. biophysical based assays, as well as in commercial ­suppliers and thus allows data ­management for drug discovery The new Quality by Design approach vitro disease models based on induced detailed, mechanism-based­ research. data analysis workflows, which ­integrate implemented at our Frankfurt am pluripotent stem cells. This allows us to The following platforms are available project, public and proprietary data. Main location addresses the complex investigate target “druggability” and to our customers: Preclinical disease We further develop algorithms and AI challenges posed by clinical trials in an enables mechanism of action studies. models, epigenetics and optogenetics, tools for the statistical analysis of patient attempt to reduce exclusion rates. The The “Fraunhofer IME Repurposing biomedical analysis, protein engineer­ and virtual patient cohorts in the areas combination of excellent study design Collection” of over 5,500 small mole- ing, predictive clinico-pharmacological of diabetes, ageing research and - in and expertise in specific indications is a cules, also offers an alternative path to models, data bionics, pharmaceutical ­collaboration with Germany-based unique character­istic of this group. quick clinical application. As a screening technology and human pain models. ­cancer registries - in oncology. partner site in the EU-OPENSCREEN infrastructure, we provide access to synthetic chemistry, chemical proteomics and structural biology platforms.

Translational Medicine: Research, Development and Services TM TM TM TM Dr. Philip Gribbon Dr. Volker Laux Prof. Dr. Carsten Claussen PD Dr. Frank Behrens www.ime.fraunhofer.de/en/TM/RDS [email protected] [email protected] [email protected] [email protected]

18 19 INSTITUTE MANAGEMENT AND LOCATIONS MOLECULAR BIOTECHNOLOGY DIVISION

31.12.2019 Head: Prof. Dr. Stefan Schillberg

Executive Director Aachen Münster Head of Administration Prof. Dr. Dr. Gerd Geißlinger Dietmar Douven Phone +49 69 6301-7620 Molecular Biotechnology Functional and Applied Genomics Phone +49 241 6085-11030 [email protected] Prof. Dr. Stefan Schillberg Prof. Dr. Dirk Prüfer [email protected] Phone +49 241 6085-11050 Phone +49 251 832-2302 [email protected] [email protected] Members of the Institute Management (acting) Prof. Dr. Christoph Schäfers and Prof. Dr. Stefan Schillberg

Bioprocess Engineering Dr. Dr.-Ing. Johannes Buyel Phone +49 241 6085-13162 [email protected]

Industrial Biotechnology Dr. Stefan Jennewein Phone +49 241 6085-12120 [email protected]

Plant Biotechnology Plant Biotechnology Dr. Stefan Rasche Holger Spiegel Phone +49 241 6085-12321 Phone +49 241 6085-12461 [email protected] [email protected]

20 21 APPLIED ECOLOGY AND BIORESOURCES DIVISION

Head: Prof. Dr. Christoph Schäfers

Schmallenberg Gießen

Applied Ecology Bioresources Prof. Dr. Christoph Schäfers Prof. Dr. Andreas Vilcinskas Phone +49 2972 302-270 Phone +49 641 97219-100 [email protected] [email protected]

Ecological Chemistry Natural Product Research Biodiversity Research Dr. Dieter Hennecke Prof. Dr. Till Schäberle Dr. Eileen Knorr Phone + 49 2972 302-209 Phone +49 641 97219-140 Phone +49 641 97219-160 [email protected] [email protected] [email protected]

Bioaccumulation and Food- and Feed Improvement Ecotoxicology Animal Metabolism Agents Biological Plant Protection Dr. Elke Eilebrecht Prof. Dr. Christian Schlechtriem Prof. Dr. Holger Zorn Dr. Kwang-Zin Lee Phone +49 2972 302-144 Phone +49 2972 302-186 Phone +49 641 97219-130 Phone +49 641 97219-150 [email protected] [email protected] [email protected] [email protected]

Environmental Specimen Bank Product Development, Ecotoxicology and Elemental Analysis Expression and Formulation Insect Farming Matthias Teigeler Dr. Heinz Rüdel Prof. Dr.-Ing. Peter Czermak Dr. Dorothee Tegtmeier Phone +49 2972 302-163 Phone +49 2972 302-301 Phone +49 641 97219-120 Phone + 49 641 97219-170 [email protected] [email protected] [email protected] [email protected]

Environmental and Food Analysis Quality Assurance Prof. Dr. Mark Bücking Dr. Cornelia Bernhardt Phone +49 2972 302-304 Phone + 49 972 302-137 [email protected] [email protected]

22 23 TRANSLATIONAL MEDICINE DIVISON

Head: Prof. Dr. Dr. Gerd Geißlinger

Frankfurt am Main Hamburg

Biomedical Analytics and Imaging Digital Health Research Prof. Dr. Dr. Gerd Geißlinger Prof. Dr. Carsten Claussen Phone +49 69 6301-7620 Phone +49 40 303764-277 [email protected] [email protected]

Drug Discovery Dr. Philip Gribbon Phone +49 40 303764-271 [email protected] Drug Research Prof. Dr. Dieter Steinhilber TM Phone +49 69 798-29324 [email protected] Assay Platforms Dr. Ole Pless Phone + 49 241 6085-13162 [email protected] Drug Formulation Prof. Dr. Jennifer Dressman Phone +49 69 798-29680 [email protected]

Translational Drug Validation Dr. Volker Laux Phone +49 69 8700-25076 [email protected]

Clinical Research PD Dr. Frank Behrens Phone + 49 69 6301-7302 [email protected]

25 INSTITUTE DATA

Budget Total budget of Fraunhofer IME Employees of Fraunhofer IME

In 2019, the operating budget of ­Fraunhofer IME increased to a previously unreached level of 41.8 million euros. In addition, about 2.8 million euros were invested in equipment. Fraunhofer IME again recorded a significant increase in construction activities (approx. 15.6 million euros), primarily due to the ­construction of the new institutes in ­Gießen and ­Schmallenberg.

67.5 percent of the budget was financed by external income, or 77.7 percent if the locations in Gießen and Frankfurt am Main, which are mainly financed by the federal state, are included.

Economic earnings of 14.1 million euros Personnel remain at a constantly high level. This External financing of Fraunhofer IME corresponds to an economic revenue At the end of 2019, 533 personnel were employed at the Fraunhofer IME locations in Aachen, share (Rho Wi) of 41.0 percent and 33.8 Münster, Schmallenberg, Gießen, Frankfurt am Main and Hamburg. percent respectively. In 2019, 53.7 percent of Fraunhofer IME personnel were female.

Thus, in 2019, Fraunhofer IME once again achieved excellent results in the key figu- res of the Fraunhofer-Gesellschaft.

26 27 OUR RESEARCH

The radiokitchen – Quo vadis, molecule?

Colorful potatoes

Translation of research into medical applications

Insect virulence inhibitors for the therapy of lung infections

Recycling CO2 emissions with bacteria

Using artificial intelligence to predict biological age

»2«

Fraunhofer IME is one of the first ten institutes to succeed in the turbulent early days of the Fraunhofer-­Gesellschaft.

29 THE RADIOKITCHEN – QUO VADIS, MOLECULE?

Food processing often comprises For an authorisation of plant protection products, their fate during food processing is currently­ many complex steps. ­simulated only by heating the active substance in water. A new laboratory at Fraunhofer IME now ­allows the performance of complex studies under realistic food processing conditions. First results show ­significant differences between current simulation procedures and reality.

A predominant portion of our food is processed prior to ­during food processing is of high interest for food safety. To In a third trial, potatoes were treated with the ­sprouting identification of potentially relevant new degradation prod­ consumption. The desired properties of most foodstuffs ­investigate this fate the current registration procedure only ­inhibitor chlorpropham and were stored for up to six ucts. Radioanalytical methods will be further used to better are only obtained after cooking, baking or roasting steps. requires heating of an active substance in water at maximum months. At different points of storage, individual tubers were understand chemical reactions during food processing. For Complex chemical reactions occur during food processing temperatures of 120 °C. Higher temperatures, as obtained ­withdrawn and boiled (100 °C), fried (170 °C) and baked example, in a current project in cooperation with the Monash and can lead to the formation of desired colouring or aroma for example during baking or frying processes, or chemical (200 °C). In contrast to the opinion of the European Food University in Australia we aim to elucidate the fate of nutrients components. Also, hazardous substances like acrylamide can reactions with food ingredients are not considered so far. In Safety Authority no formation of the important compound during food processing. In this project, potential effects of be produced during such processes. Due to the ­enormous a project in cooperation with ­Fraunhofer IVV we ­investigated ­3-chloroaniline was observed during potato processing. processing-induced degradation products on human health complexity of food processing the elucidation of such food how simulation studies compare to ­realistic ­processing steps. ­Chlorpropham residues in edible products were reduced by 73 are investigated. chemical reactions often takes several years. A special to 83 percent during the different processing steps. ­laboratory kitchen – the radiokitchen – at Fraunhofer IME now allows the performance of complex and realistic food Simulative trials often far from reality The results clearly show that complex food chemical reac- processing procedures using radiolabelled substances. The use tions during food processing cannot be reduced to simple of highly specific tracing of radioactivity of a substance and its When heating the fungicide prochloraz in rapeseed oil, an heating experiments of substances in water. The tests with degradation products can significantly speed up such studies extensive degradation of the active substance was already­ prochloraz in heated oil show that the reactions can be much in comparison to current approaches. ­demonstrated in preliminary tests. The radioactive label more ­complex. At the same time, tests with deltamethrin and ­allowed an insight into the complexity of the degradation chlorpropham show that an increase in temperature and the ­process. For the first time, processing-induced chemical presence of a matrix do not necessarily constitute a worst Plant protection products and food processing ­reactions between an active ingredient and food ­ingredients case scenario. Future tests are planned to investigate how the like fatty acids and glycerol were proven. In total, the complexity of food processing for the authorization of plant Almost every conventionally grown agricultural product is ­formation of eleven degradation products was observed. Many protection products can be simplified to a few model tests. AE ­treated with plant protection products. These agrochemicals of these were described for the first time. Thedegradation ­ The identification of worst case scenarios can further increase TMBR serve as an integral part of modern agriculture. Even after process was found to be highly dependent on temperature, food safety and consumer protection. Bernd Göckener ­correct application, residues of plant protection products in heating time and the type of oil used. In the simulation trials, [email protected] agricultural raw products cannot be avoided. To assess the however, a minor degradation with only a single degradation potential risks of active substances and their degradation product was reported. During high-temperature heating of Tracing radioactivity as a shortcut ­products to humans, animals, and the environment, active ­tomato products the insecticide deltamethrin also showed substances undergo an extensive registration and ­approval high discrepancies to the results of simulation ­trials. In the Furthermore, the results show enormous advantages of radio­ procedure. This includes complex studies to elucidate the ­frame of the current procedure a broad degradation of the analytical methods compared to normal techniques. The trac­ fate and the action of substances in plants, animals, and active substance was described. Despite temperatures of up ing of radioactivity allows the ability to obtain a full ­balance the environment. As many foodstuffs are processed ­prior to 250 °C, deltamethrin was found to be stable during the of the residues of the active substance and its ­degradation to consumption, the fate of plant protection products heating of tomato paste. products.2 Also, this technique facilitates and ­accelerates the

30 31 COLORFUL POTATOES

Anthocyanin-rich potatoes in Colorful potatoes are not only beautiful to look at, but also health-promoting, since they contain larger the field and on the market. quantities of colored, secondary plant substances, so-called anthocyanins, than their pale counterparts. In order to make these anthocyanins accessible to many people, the project “MoMaPo“ (Molecular ­markers for the generation of potatoes with enhanced anthocyanin content) is developing molecular tools for the targeted breeding of such potatoes.

Secondary plant compounds in human nutrition and give the radiant energy as heat. This is how proteins and Potato breeding with molecular tools represents the ­extraordinary biodiversity of Chilean potatoes. DNA molecules in the cells are protected from the harmful An important part of this gene bank are the potatoes ­collected Even in industrial nations with an excellent food supply and effect of the UV rays. In addition, the intense coloring attracts Potato breeding is a complex process and in particular in the area of Chiloe Island, which are ­characterized by a variety, fruit and vegetable consumption is often relatively low insects and other animals. They ensure the propagation and the ­genetics of quantitative traits such as the anthocyanin ­particularly high diversity in the ­characteristic of colored and well below internationally recommended levels. We cover distribution of the plant. The anthocyanins also have a strong content in tuber flesh is difficult to resolve. New varieties are mark tubers. 290 of these plants were analysed for ­potential the majority of our diet with a few basic foods such as rice, antioxidant effect. If the plant is exposed to oxidative stress, ­developed by combination breeding by crossing two varieties ­markers of ­increased anthocyanin content. The results corn, wheat and potatoes. A human diet based predominantly free radicals are produced, which react with oxygen ­molecules or clones with desired properties. The crossing and selection obtained were then ­bioinformatically associated with the on plants can make a valuable contribution to human health, to form reactive oxygen radicals and exert a negative influence­ processes for the generation of a new potato variety in the anthocyanin content ­determined, so that molecular mar- especially if it is based on fruit and vegetables, since plant-­ on the metabolism of the plant. Free radicals are also classical way takes about ten years. kers could be identified which may be used in the future for based food always contains secondary plant substances in ­suspected to be associated with various diseases in humans. ­breeding new potato varieties with coloured tuber flesh. addition to the classic macronutrients carbohydrates, proteins Anthocyanins are able to render free radicals harmless and By the use of molecular markers for different ­characteristics, and fats. are therefore said to have health-promoting effects. Studies this process can be significantly shortened. Early in the in humans and animals have shown that anthocyanins have selection process, those offspring can be selected that will Secondary plant compounds are organic compounds that anti-inflammatory, anti-viral and anti-carcinogenic properties. develop the desired characteristics. For example, plants could AE are mostly found in specialized cells, where they play an In addition, positive effects on cardiovascular disease, obesity, be selected that are resistant to certain diseases without TMBR important role for the entire plant, e.g. in protection against increased cholesterol levels and memory performance were the necessity to carry out very complex resistance tests in predators or through their attractive coloring. Many of the observed. the field or greenhouse. Such an approach is known as secondary plant compounds also have positive effects on marker-­assisted selection or “smart breeding“. The use of human health, which scientists know they can use. For Most staple foods, such as wheat or rice, are relatively poor in such markers is ­indispensable for certain characteristics. If, ­example, most ­pharmaceuticals are based on plant secondary anthocyanins, so fruit and vegetables are currently the main for example, colored landraces are crossed with uncolored MB TM metabolites. But even today, the mechanisms of action of source of anthocyanins in human nutrition. Potatoes are an elite varieties, uncolored offspring can develop because Dr. Jost Muth some secondary plant metabolites are still unknown. A large exception, as old, lesser-known blue- and red-­fleshed potato ­i­mportant alleles for anthocyanin production split off. In order [email protected] group of secondary­ plant substances are the water-soluble varieties whose color is due to the presence of anthocyanins to restore the ­characteristic high anthocyanin content, lines anthocyanins, which belong to the group of flavonoids. They exist, in addition to the yellow- and white-fleshed ones. ­containing ­different complementary alleles must be combined­ are found in cell sap of almost all higher plants. They mostly Especially in South America there are still many colored old in further crosses. Therefore, such advantageous alleles also occur in the flowers and fruits, where they are responsible landraces to be found, which can be used for the breeding must be identified­ at the molecular level in order to provide for the partly intensive red, violet or blue coloring. Hence, their of modern efficient potato varieties with a high content of the ­necessary tools for such breeding, which is the primary name. It consists of two parts: Ánthos, the ancient Greek word anthocyanins. goal of the binational cooperation project “MoMaPo“. The for flower, and kyáneos, the ancient Greek word for dark ­participating partners Universidad Austral de Chile, ­Fraunhofer blue or dark color. Anthocyanins have three main functions in Chile Research and Fraunhofer IME were able to use the plants: They absorb the short wavelength UV light of the sun potato gene bank of the Universidad Austral de Chile, which

32 33 TRANSLATION OF RESEARCH INTO MEDICAL APPLICATIONS

The “Critical Path Concept” is Drug development is closely linked with the identification of endogenous molecules as targets for designed to support researchers therapeutic agents. However, the relevance of these molecular targets for the treatment of the specific in developing a validation pro- disease must first be proven. This target validation process requires standardized, robust, reproducible cess for their project. and high quality testing procedures. Fraunhofer IME is part of a consortium that for the first time has developed guidelines for optimizing such a process.

The challenge in biomedical research ­standards in target validation within the academic environ- things, quality aspects such as the blinding of studies and tools, the GOT-IT recommendations should be made ­available ment. the calculation of the sample size have been taken into to a broad user group. They should support academics in Despite the diversity of medicines, the effective treatment of account in only a very few studies. Based on the results of implementing industry-like processes for target validation and many diseases is either inadequate or impossible. ­Although the literature analysis, guidelines were developed in dialogue make an important contribution to improving the quality and the medical demand is very high, no new drugs for the The GOT-IT guidelines with other scientists together with experts from industry and applicability of academic research results. ­treatment of diseases like Alzheimer's have reached the transfer societies. These guidelines are already being taken market for years. The medical community is also desperately At the level of funding bodies, the message has also been into account for the evaluation of project proposals for new searching for new antibiotics, yet the big pharmaceutical heard that the translation of academic research results into BMBF funding measures. ­companies recently announced their withdrawal from this medical applications must be improved and promoted. research area. The guidelines were designed to be applicable to as With the “National Drug Initiative“, the Federal Government­ many clinical indications as possible - from infection In the scientific world and even in society, the “reproducibility has set itself the goal of strengthening drug research to ­neuroscientific research. The GOT-IT consortium has crisis” in biomedical research has been an intensively discussed and ­promoting the development of new drugs. As part ­defined “validation blocks” for the guidelines, which issue for a long time. This unsatisfactory situation is at least of this initiative, the Federal Ministry of Education and should be taken into account when developing a project. partially responsible for the deficit in the implementation of Research (BMBF) has already provided various funding They ­address the link between target and disease, safety potential targets for drug development. measures ­dealing with the topic of target validation. The aspects, ­innovation and technical feasibility. For each of TM project ­“Guidelines On Target Validation for Innovative these ­validation blocks critical questions are suggested, the Dr. Martine Hofmann The discovery of such biological targets is the basis for the ­Therapeutics“, or GOT-IT for short, was developed as part of answers to which should help the researcher to identify the [email protected] ­development of novel drugs. Knowledge about new targets these extensive funding ­measures. A consortium ­consisting most relevant aspects of the validation process to address for TM originates mainly from basic research at universities and of scientists from the Charité in Berlin, the consulting firm a specific project. With these tools, the researcher should be non-university research institutions. This is where ­discoveries PAASP in Heidelberg and Fraunhofer IME in Frankfurt am able to develop an individual project-related critical path. are made that shed light on fundamental pathological Main has developed guidelines for robust target validation­ ­processes leading to the development of diseases. In order to that can be used and implemented in the academic be able to translate this knowledge into clinically applicable ­environment. Online tools therapeutic approaches, validation of the target according to industrial standards is mandatory. Such validation processes Initially, the consortium carried out a comprehensive anal­ Currently, online tools are being designed to develop must be robust, reproducible and well documented. They must ysis of the scientific literature on target validation. In this ­structured plans for a target validation project. In addition, be carried out under defined quality conditions and be backed process, different priorities were set, such as the relevance the GOT-IT consortium is creating a learning application for TM up by sufficient statistical evidence. A major reason for the of the model organism used, the number of test systems young academics involved in target validation and an online lack of application of suitable approaches from basic research and evaluation methods employed, and the application of networking platform where academic and industrial scientists is lack of knowledge of these industrial requirements and various quality criteria. The results show that, among other 2can interact with each other (www.got-it.app). With these

34 35 INSECT VIRULENCE INHIBITORS FOR THE THERAPY OF LUNG INFECTIONS

The larvae of the greater wax The researchers used bioreactors Thermolysin-like metalloproteases such as pseudolysin (Pseudomonas aeruginosa) are highly toxic and moth produce a large repertoire to produce larger quantities of are considered important virulence factors, since humans do not have any endogenous inhibitors against of antimicrobial peptides. IMPI. these bacterial enzymes. So far, the only selective virulence blocker has been discovered in the larvae of the greater wax moth, Galleria mellonella - the Insect Metalloprotease Inhibitor (IMPI). IMPI is used to develop a new therapeutic approach against lung infections.

Alternative therapeutic approach for the treatment of a prominent role. These are not only essential as virulence cleavage, between amino acids N56 and I57, by the protease successfully implemented to obtain a pure product and lung infections factors, they also cause symptoms associated with infections and reversibly inhibits protease activity. ­remove endotoxins. such as haemorrhagic bleeding, necrosis and sepsis. However, In Europe, more than 33,000 people die each year from the inhibitors of M4 metalloproteases that have been tested so Efficacy and toxicity studies of the IMPI are performed by the ­infections with resistant pathogens. The identification of far are not suitable for the development of new anti-infectives, Biotechnological production of antimicrobial peptide cooperation partner, the Fraunhofer Institute for Toxicology new active ingredients with antibacterial activity and their as they also inhibit human matrix metalloproteases and can and Experimental Medicine ITEM in Hannover. Once suitable development into antibiotics is very costly and involves a high therefore cause serious side effects. The search for innovative With the development of a new therapeutic approach against cell infection models have been established, the effectiveness risk. Effective new strategies to combat resistant pathogens virulence blockers is thus focused on molecules that act highly lung infections, based on the IMPI molecule, the excessive use of optimized IMPI variants against the pathogen P. aeruginosa are ­urgently needed - especially in lung infections, which are specifically against thermolysin-like metalloproteases without of broad-spectrum antibiotics will be simultaneously reduced. can also be investigated in the form of a combination therapy among the leading causes of death according to the ­World inhibiting human enzymes. The only selective inhibitor of In order to investigate the potential effect of IMPI in more with antibiotics or other potential antimicrobial peptides. This Health ­Organization (WHO). One of the most common microbial M4 metalloproteases described so far is a peptide detail, a suitable manufacturing process had to be ­developed allows a further extension of the efficacy range for evaluation TM ­pathogens in hospitals that develop resistance to antibiotics derived from insects, the Insect Metalloprotease Inhibitor first. For this purpose, the bacterial expression system in in vitro and in vivo models of pneumonia with antibiotic-­ used in hospitals is the gram-negative bacterium Pseudomonas (IMPI). Within the BMBF-funded project ”Inhalable Virulence ­Escherichia coli was chosen. Due to the complex folding of resistant pathogens. aeruginosa. This bacterium initially attaches itself to a region Inhibitors from Insects for the Therapy of Lung Infections” the peptide, only selected strains are suitable for production - where the host's defence mechanism is already weakened (4-IN), the optimization of IMPI and its preclinical testing with these strains are capable of forming the five disulfide bridges, (e.g. by trauma, burns, surgery, etc.). Extracellular virulence regard to its potential as a novel agent for the prevention and which are crucial for the successful inhibition of M4 metallo- factors are then released, causing further damage to host treatment of lung infections is addressed. proteases. tissue until the bacterium enters the host's bloodstream and spreads throughout the body. As the infection progresses, With regard to the development of a production process the attached colonies form a biofilm that provides effective IMPI - antimicrobial peptide from Galleria mellonella for biopharmaceuticals, the media development for the ­protection against the host's immune response. ­fermentation was exclusively carried out using chemically IMPI is an isolate from the larvae of the greater wax moth, defined substances. An optimization of the media ­formulation Virulence factors are essential for infection and their persisten- Galleria mellonella, which are capable of producing a large as well as the process parameters by means of statistical AE ce and the selective inhibition of these factors is an attractive repertoire of antimicrobial peptides. As part of the humoral design of experiments led to the development of a fed-batch TMBR new strategy in the fight against emerging antimicrobial immune response to an infection caused by bacterial or fungal process with high cell densities during IMPI production. The Dr. Doreen Gerlach resistance. This approach of an alternative treatment strategy pathogens, IMPI was isolated from the larval hemolymph. transferability of the fermentation process was ­demonstrated [email protected] does not focus on the immediate killing of the pathogens, The characterization of the IMPI revealed a peptide stabilized after establishing suitable scale-up criteria from 0.5 L to 7.5 but on the neutralization of their pathogenicity or virulence by five disulfide bridges and about 8 kDa in size, its mode of L and 20 L scale. In addition to recombinant production, the factors. Pseudolysin, one of the crucial virulence factors of P. action is based on its binding to the active site of the metallo­ focus of process development was also on the ­establishment aeruginosa, is an M4 metalloprotease. Among the bacterial protease. Due to the five disulfide bridges and molecular of a suitable purification method. In the course of this DSP exotoxins, metalloproteases belonging to the M4 family play interactions with the protease, IMPI retains its structure after 2development, a chromatographic purification strategy was

36 37 RECYCLING CO2 EMISSIONS WITH BACTERIA

Steel plants emit tons of CO, The number of passengers is

Microorganisms are tiny all-rounders. They are able to produce numerous substances from a wide ­variety CO2 and H2 as off-gas, a valuable constantly increasing - the goal of chemical substance classes. Even when using different substrates, they are not picky. It is therefore substrate for some bacteria. is a sustainable production of possible to use them as microbial cell factories in order to produce useful basic chemicals and fuels from jet fuel. exhaust gases using biotechnology.

The vast majority of scientists worldwide agree - ­climate Stable integration of non-native biosynthetic pathways the gas-fermenting clostridia. A gas mixing system for the ­production of the desired molecules on an industrial scale. In ­change is man-made. The use of fossil resources for the into the genome of Clostridium ljungdahlii testing of different gas compositions was installed. Further- addition to the extraction of chemicals for the production of ­production of basic chemicals and fuels releases large more, first process parameters were improved. As part of a jet fuels, there are numerous other industrial applications. We amounts of carbon dioxide (CO2). As a result, fossil ­resources Not all desirable products can be produced by the Fraunhofer-Gesellschaft funded MAVO project, the products are currently working on several projects with different ob- are ­depleting and the concentration of CO2 in the air ­rises ­bacteria recycling the gas. By introducing genes of known resulting from gas fermentation with clostridia were purified jectives: The EU-funded H2020 project BIOCON-CO2 ­focuses,

­continuously, accelerating climate change with all its negative­ ­biosynthetic pathways, the product spectrum can be and chemically processed in collaboration with Fraunhofer ICT among other topics, on the utilization of CO2 to produce effects. In 2018 alone, around 4.4 billion ­passengers were ­considerably ­expanded. An intermediate product common and Fraunhofer UMSICHT. After oligomerization of acetone, isopropanol, butanol and hexanol, and the BioCOnversion transported by aircraft and 359 billion liters of jet fuel were to all ­organisms serves as the starting substrate for these butanol and hexanol, it is now feasible to obtain a complex project coordinated by CLIB and funded by the BMBF pursues ­consumed, and the numbers are increasing. But what can we ­”imported” biosynthetic­ pathways: Acetyl-CoA. It can then be high-molecular mixture that can serve as drop-in fuel for the utilization of CO from steel plants to produce a plastic do if society does not want to do without everyday things ­enzymatically converted into a product in several steps. The aviation fuel. precursor. and travel? One option is to use alternative ­sustainable basic chemicals obtained in this way need to be extracted and ­biotechnological ­production processes. Bacteria possess can subsequently be processed chemically for ­manufacturing ­biosynthetic pathways for a large number of chemical everyday products. Acetone is converted into plexiglass, Metabolic engineering and optimization in current ­substances. For example, bacteria of the genus Clostridium ­isoprene into rubber, and ethanol, butanol and hexanol into projects can produce solvents such as acetone, but also acids such as fuel. acetic acid and a number of alcohols such as ethanol, butanol Based on the promising results of the MAVO project on the and hexanol. Traditionally, sugar extracted from plants is used In order to establish the somethimes very complex biosynthetic targeted genetic modification of bacteria for the ­production as the substrate in this process. In order to feed a growing pathways in the cells, the genes of the biosynthetic pathway of specific basic chemicals and their further processing, world population, industrial raw materials must not compete are introduced as DNA fragments and integrated into the ­additional projects in this field are underway. Following proof- with the production of food. Furthermore, they must be cheap ­genome in order to obtain a stable production strain. In this of-­concept, the cells are now being optimized to ­increase MB and available in large quantities. One part of the solution way, the use of antibiotics as selection markers for cultivation­ product yields. Possible bottlenecks in the biosynthetic Dr. Gabriele Philipps could be the recycling of off-gases from the steel industry. are not necessary. The development of methods for the pathway no ­longer remain a black box, but can be ­identified [email protected] ­Large ­quantities are generated during steel production - transfer and integration of large biosynthetic pathways in C. by ­transcriptome, proteome and metabolite analyses. In around 1.4 tons of CO2 are emitted per ton of steel. These ljungdahlii was established at Fraunhofer IME and was recently addition to the ­identification of more efficient enzymes for the gases also ­consist of carbon monoxide (CO) and hydrogen published in the journal "Biotechnology for Biofuels". biosynthetic pathway used, alternative competing biosynthetic

(H2). Certain bacteria such as Clostridium ljungdahlii are able pathways can be eliminated by using methods employed at to use CO2 and CO as a source of carbon for their growth Fraunhofer IME for these organisms, such as random chemi- and the ­production of various metabolic products. CO and Proof-of-concept: From off-gases to jet fuel cal mutagenesis or ­directed mutagenesis using CRISPR/Cas9.

H2 serve as an energy source. How do you get the bacteria The product ­quantities are analyzed by GC-MS-MS to screen to ­synthesize specific substances and furthermore to produce A fermentation system was optimized for the utilization of for the best strains. The aim is to identify production strains large ­quantities of these? the toxic and potentially explosive gases CO, CO2 and H2 by that2 are ­suitable to ensure an economical and sustainable

38 39 USING ARTIFICIAL INTELLIGENCE TO ­PREDICT BIOLOGICAL AGE

KNIME workflow for analysing The global average life expectancy is currently at its highest, which has largely been driven by medical­ provided epigenetic data. advancements. In ageing populations, the quality of life may be compromised and measures can be taken which will reduce the risk of being afflicted by diseases through diet and exercise. One relatively new addition in determining the health of an individual at the cellular level makes use of advanced ­sequencing technologies and artificial intelligence. Our cutting edge research is presented herein.

Correlating epigenetic changes with the ageing process of an individual. Our algorithm is subsequently utilized to Modulation of the ageing process – making this a reality outputs of the Proof-of-Concept screening have successfully enabled by advanced sequencing technologies ­analyze the CpG data and predict the biological age of an indi- using in vitro techniques and artificial intelligence yielded compounds which are modulators of the targets of vidual. Overall, the methylation of 800,000 sites are measured interest. As these have been shown to be linked to biological The genetic code is largely constant throughout life. ­However, and our algorithm has been refined such that we only require The above research has led to the identification of 30 genes ageing, we propose to initiate screening campaigns for each in the epigenetic code, significant changes do occur, which CpG sites of 130 genes to reliably predict the ­biological age. whose profiles alter during ageing. This is exemplified by the target using larger compound libraries in order to identify encompass heritable changes in gene expression that do not It is to be noted that 30 of these genes code for proteins for Gene Radar plots for a 9 year old and a 78 year old individual. novel compounds. Fraunhofer IME is currently working closely involve changes to the underlying genetic code. Epigenetic­ which assays are available to monitor their functional activity. with Cerascreen GmbH to secure funding for this work and changes are now known to be a regular occurrence In addition, small ­molecule modulators for these 30 proteins hope to identify new compounds that offer the potential to ­influenced by many variables such as age, lifestyle, disease have been reported in the literature, which demonstrates their halt or even reverse the ageing process. In order to protect the and environmental­ factors. One of the most widely studied druggability. These proteins are currently being evaluated as intellectual property that has been generated from this project, epigenetic changes is methylation of the genetic code. This drug targets with the aim of identifying chemical modulators a PCT patent application has been submitted. process involves the transfer of a methyl group (CH3) to the C5 which may halt or even reverse biological aging. position of cytosine,­ forming 5-methylcytosine (5mC), which are also known as CpG sites. Methylation of genes has a direct impact on gene expression and there is growing evidence that it correlates with the biological age of an individual and may not correspond to the number of years a person has been ­alive, namely their chronological age. We have ­worked TM in ­collaboration with Cerascreen GmbH and developed an ­algorithm that can successfully predict an ­individual’s Dr. Sheraz Gul ­biological age from the epigenetic profile of the DNA [email protected] ­extracted from a saliva sample. The biological age can be used as a surrogate for the health of an individual in a broad sense. Graphic User Interface for the Biological Age Test. The Gene Radar Comparison of the methylation (red dots) of 30 genes for a 9 Below is a description of the Biological Age test developed in a plot indicates the extent of methylation for each of the 30 genes (above) and 78 year old (below) individual. Orange area: Average ­collaboration between Fraunhofer IME and Cerascreen GmbH. correlating with ageing. methylation across all ages.

Fraunhofer IME has developed a Graphical User Interface In a Proof-of-Concept study, five druggable protein targets The Biological Age Test workflow and output (GUI), which provides a visual representation of the ­epigenetic (from the above mentioned 30 genes) were prioritized and profile of an individual. The capabilities of the GUI will be miniaturized screening compatible assays were developed. TM TM Following extraction of DNA from each saliva sample, we use expanded to include analysis of additional health related These were subsequently screened against a library of 800 Andrea Zaliani the Illumina sequencing platform to determine the CpG profile information. chemical2 compounds with known safety properties. The [email protected]

40 41 IN DIALOG

An Interview with Dr. Kwang-Zin Lee

Background Dr. Kwang-Zin Lee studied biology at the Eberhard Karls University in Tübingen. After his doctoral thesis at the Max Planck Institute for Developmental Biology, he conducted several research stays abroad, including at the University of Western Ontario in Canada, the Centre d'Immunologie de ­Marseille-Luminy and the Insitut de biologie moléculaire et cellulaire in Strasbourg, France. Since 2016 he is working at the Branch for Bioresources at the Fraunhofer Institute for ­Molecular Biology and Applied Ecology IME in Gießen, Germany. There he established the research group for insect pathogens. In 2017, he took over as head of the Biodiversity department and established the new department of Biological Plant Protection at Fraunhofer IME in Gießen, of which he is head since 2018. His goal is to develop customized solutions for biological plant protection from natural insect pathogens such as bacteria, fungi and viruses. »3« Bioresources

In 2009, the Fraunhofer IME project group “Bioresources” was established in Gießen under the leadership of Prof. Dr. Andreas Vilcinskas.

43 BIOLOGICAL PLANT PROTECTION: WITH MICROBES AGAINST INSECT PESTS

The spotted wing drosophila originates from Asia and has also been To develop biologically safe crop protection products, Dr. Kwang-Zin Lee and his team focus on isolating ­common in Germany since 2011. It infests fruit crops such as cherries. and developing natural antagonists of insect pests. One of the model systems used in his research is the invasive spotted wing drosophila Drosophila suzukii, which is currently responsible for major agricultural ­damage in fruit growing both nationally and internationally. Natural viruses and bacteria are isolated from the fly as microbial antagonists and tested for their suitability in biological plant protection. Dr. Lee and his colleagues are testing whether these viruses and bacteria can be used directly as biologicals are known to be important aphid antagonists. We study microorganisms such as bacteria, fungi or the effective natural substances extracted from them in modern crop protection. At the same time, and viruses. These insect pathogens generally have a high host specificity and can be specifically innovative methods for the large-scale production of the candidates in the bioprocess area are being applied against certain insect pests. The public opposition to chemical insecticides has also led developed together with partners from science and industry. to a rethink in the crop protection industry, so I believe that the future potential for biological crop protection is very high.

Dr. Lee, you studied biology. What appealed to you in this subject and your future Your team is dedicated to biological plant protection using insects. Why insects of all career? What does your everyday working life look like today? things? What specific research approaches do you pursue?

I have to go a bit further, since my childhood I have a strong interest in animals, especially Insects are one of the most evolutionarily successful and by far the most species-rich class of insects, according to my mother one of my first words was “ant“. Everything living possessed animals of all. Over a million species have been described, each of which represents a large a ­special attraction for me. It was already clear to me as a child that I wanted to become a reservoir of insect-pathogenic microorganisms. An insect pathologist therefore has an almost biologist. As my career progressed, my everyday work gradually shifted from the laboratory unlimited number of insect-pathogenic candidates and combinations for the application of to more office work. At the beginning as a research assistant I was still actively involved in the insect pathogens. As mentioned above, many insect pathogens are very host-specific, i.e. ideal ­laboratory. The tasks as a group leader can be envisaged in such a way that more time is inves- for the development of tailor-made insect control if only a defined pest is to be controlled. ted in the planning and design of projects and the resulting work packages. In addition, there We need an environmentally sound method to control insect pests, our strategy is based on the are teaching activities for the new master's course in “Insect Biotechnology and Bioresources” use of natural insect pathogens. at Justus Liebig University and various administrative tasks. We are currently isolating insect-pathogenic microorganisms regionally from harmful ­insects. For this purpose, we specifically collect sickly, so-called moribund, insects and isolate How do classical and “modern“ pest management differ? How do you estimate the their ­pathogens from them. The samples are prepared using two different methods. After potential? ­homogenization, one sample is spread directly onto culture plates and incubated to enrich bacteria or fungi. Until today, classical pest management has been based mainly on chemical insecticides. The other sample is sieved through a 0.22 µm fine filter to specifically isolate viruses. The results Unfortunately, these are accompanied by not inconsiderable undesirable side effects, such obtained with natural viruses from the spotted wing drosophila Drosophila suzukii, an ­invasive as negative effects on human health and the environment, the development of resistance of insect that is highly damaging to ripe fruit, should be highlighted. There we succeeded in harmful organisms to these insecticides and collateral damage to non-target organisms such as ­isolating and identifying a virus that has an insecticidal effect against the fly. This virus is quite bees and bumblebees. One promising approach is biological pest management. Biological plant new and has not yet been characterised in detail. We are working to extract from this virus protection involves the use of various macro- and microorganisms. The macro-organisms are with different methods by optimizing the efficacy, establishing mass production and ­developing generally predators or parasites of the harmful organisms. These are mainly insects, spiders and suitable formulations, to ultimately be able to bring a biologically safe agent against the nematodes, which are also commercially available and are actively used as beneficial insects. ­spotted wing drosophila to market maturity. The majority of beneficial insects are used for greenhouse cultivation. Ladybirds, for example,

44 45 The spotted wing drosophila In Germany, the first infestation infests soft-skinned fruits. It lays by the spotted wing drosophila its eggs inside intact fruits and was observed on wine in 2011. Why do you think Fraunhofer IME in Gießen is the ideal environment for this type ­causes enormous harvest losses. ­pesticides is usually associated with higher costs compared to chemical substances. Since we of research? cooperate with internal partners and experts in bioprocess optimization, I believe that we can find solutions that make the processes more economical. The environment at Fraunhofer IME is particularly stimulating because we have many ­colleagues with excellent expertise in a wide range of fields such as applied entomology, No, in the short term I don't see any possibility of completely dispensing with chemical pest microbiology, molecular biology, microbial genomics, bioinformatics, analytics and bioprocess control. I would see biological plant protection with insect pathogens as part of an integrative technology, and we have established excellent interdisciplinary networks to solve research pest control measure in which at least the proportion of chemical pesticides can be significantly questions and develop products. This means that we are able to map closed project cycles reduced. within Fraunhofer IME, in which every area benefits. A small example: If we isolate and identify microorganisms in our department that have no direct effects on the respective harmful insects, this is of course a pity for our research and development. But, if the microorganisms produce Finally: What do you enjoy most about your work? interesting natural substances, they might be of interest to colleagues in other departments focusing on bioresources. We can then for example pass them on to our colleagues in the Honestly: Everything! I enjoy planning, conducting and evaluating studies, interacting Department of Natural Products Research. It is particularly important for us to work closely with partners from industry, agriculture, associations and university research institutions, with colleagues who integrate our new microorganisms into Fraunhofer IME's own strain bank and ­exchanging scientific information with colleagues from the various sub-areas of insect using state-of-the-art technology, who carry out analyses of the transcriptome and genome ­biotechnology. When, after planning and carrying out the projects, the final result is a patent data for strain characterisation, who assist in the necessary tests and data acquisition for risk application or a specialist publication, this gives me great satisfaction. But I also enjoy the assessment and who are indispensable partners in the identification of new lead structures. In ­administrative activities and staff management extraordinarily. addition, through close cooperation with the Justus Liebig University and its Institute of Insect Biotechnology, as well as the THM (Technische Hochschule Mittelhessen - University of Applied Sciences), we also have strong local partners with whom we have a centre in Central Hessen in the translational life sciences that is unique in this form, both nationally and ­internationally. Through the international master's degree program “Insect Biotechnology and Bioresources“, we also inspire young ­scientists to pursue this field of research. In addition, I find direct contact with ­industrial partners, associations and farmers very important, which gives us a sharper focus on the ­development of required products and services. Fraunhofer IME is thus a mediator between basic research and industrial research, and I personally enjoy being involved in this AE ­interdisciplinary field of conflict. BR Dr. Kwang-Zin Lee [email protected] What are the advantages of biological pest management? Will we soon be able to dispense completely with chemical pest control agents?

The advantage of biological pest management processes based on microbial antagonists over conventional pest control is the generally high selectivity and thus the low risk to humans and the environment. Of course, there are also disadvantages; the production of biological

46 47 IN FOCUS

Understanding flower development - Ta r g e t e d i n c r e a s e o f p l a n t b i o m a s s ! PD Dr. Gundula Noll

»4« Plant Biopolymers

In December 2010, a branch lab was opened at the ­University of Münster under the direction of Prof. Dr. Dirk Prüfer. One ­research focus is flower development.

49 UNDERSTANDING FLOWER ­DEVELOPMENT – TARGETED INCREASE OF PLANT BIOMASS!

In times of a rapidly growing world population and a shortage of arable land, securing global food Left: The targeted suppression of flowering leads to an enormous ­supplies is one of the greatest global challenges facing humanity. In order to meet this challenge, a increase in biomass - not only under greenhouse conditions. drastic increase in agricultural production is an outstanding goal, in addition to a fairer distribution Middle: The modulation of the flowering time is a key objective of of food. Increasing plant biomass, i.e. increasing the yield of crops, is of fundamental importance in our research. this context and is consequently the focus of modern plant breeding. In the “Functional and Applied Right: To flower, or not to flower, that is the question! ­Genomics” department of Fraunhofer IME at the locations Aachen and Münster, we investigate the floral induction mechanisms of plants. Based on this knowledge, we can increase biomass and yield of plants using modern breeding methods. The timing of flower induction in plants is a tightly ­regulated Flowering Locus T (FT) – the key regulator of flower process, as it determines the reproductive success of the development ­respective species. Both external environmental stimuli ­(exogenous factors), such as the day length or a man- As early as the 1930s, botanists in pioneering studies on floral datory exposure to cold, as well as internal (endogenous) induction concluded that there must be a mobile flowering factors, such as the age of the plant, play important roles ­stimulus - a so-called florigen - which is formed in the leaves in this ­regulation. Even though the basic factors of flower and then transported to the tip of the shoot. Here it termi- ­induction are similar in many plants, this is a species-specific­ nates the vegetative growth of the plant by mediating the ­process, ­since the architecture of the plant body, the ­habitat transition from a vegetative to a reproductive meristem. Many and the age entering the flowering stage are often very decades later, this mobile stimulus of floral induction was ­different. Thus, a basic understanding of the decisive ­factors described on a molecular level as Flowering Locus T (FT). and ­processes is of fundamental importance, ­especially for ­conventional, but also for alternative, novel crops, as In innumerable plants, his regulator is formed in the they directly influence the yield. The rapidly growing ­world ­conductive tissues of the leaves and then transported via the ­population and the effects of ­climate change, such as phloem from the leaves to the apical meristem of the shoot ­prolonged periods of drought or ­flooding, are the driving tip(s). Here FT interacts with its partner, the so-called FD, forces behind modern plant breeding in terms of increasing and subsequently activates all processes necessary for floral yields and producing more adaptive plants. ­induction and flower development. Although FT is the central module of floral induction across species, it is ­regulated by The central factor of flower induction of almost all plants diverse factors in different plant species. ­Depending on the ­studied to date is responsible for triggering the entire cascade location of the plant, day length plays a decisive role in the of flower formation and development: This so-called Flowering availability of FT, while other plants need a period of cold Locus T (FT) is within the focus of our research group. We aim (winter) to activate FT and initiate their flowering process. Our to understand how FT is ­regulated, along with its downstream research group is working on elucidating the mode of action genes. Ultimately, we hope to be able to increase the biomass of FT in plants of the Solanaceae family. This includes our External environmental factors and internal plant processes determine the timing of flowering. and thus the yield of crops by specifically modulating FT. model plant tobacco as well as important crop species such as This process is strictly regulated, as it is essential to ensure the existence of the respective species. At the molecular level, all these factors potato and tomato. target the expression of FLOWERING LOCUS T (FT), a central mobile stimulus of flower induction described in many species. For our model species tobacco we could identify a special case of FTs: In addition to flower-activating FTs (FT4-5), tobacco also possesses flower-inhibiting FTs (FT1-3), which are transported via the phloem into the shoot apical meristem (SAM) where they compete for FD and thus determine the optimal flowering time.

50 51 Leaf biomass of an unmodified Significantly increased leaf tobacco plant cultivated at 15 °C ­biomass of an FT-optimized increased temperature and tobacco plant cultivated at normal irrigation. 15 °C elevated temperature and normal irrigation.

Yield increase by targeted modulation of activators and Even under stress, FT-optimized plants still maintain could further increase the yield of potato plants even under repressors of flower induction their positive agronomic traits ­changing environmental conditions. This project again shows that the combination of basic Our research already resulted in the identification and In view of global climate change and the steadily increasing ­research to elucidate the function of various key factors in ­characterization of several FTs. In addition to the FTs that world population, plants that are more resistant or tolerant to ­flower development with the goals of applied research, such ­activate floral induction, we also identified a special case of FTs changing environmental conditions such as heat and drought as the targeted breeding-based optimization of these key in these plant species: These are FTs preventing the formation will be indispensable for securing the food supply. ­factors, is a central, successful and effective approach. In of flowers, i.e. repressing them. This is in a similar form only Our latest studies show that plants in which we have reduced terms of modern plant breeding, this represents a particular described for a few other crops like sugar beet or sunflower. the levels of activating FTs using modern breeding methods incentive and a major challenge. Based on the molecular characterization of FTs that have a maintain their positive agronomic traits such as increased repressive effect on floral induction, a special focus of our biomass and seed production even under various abiotic stress current work is on the use of genetic engineering to achieve a conditions. Normally, tobacco plants exposed to temperatures­ remarkable increase in plant biomass. only 5 °C higher than normal conditions are significantly ­retarded and leaf biomass is substantially lower. FT-optimized By specifically modulating the plant, we have succeeded plants generated with our technique, even when grown at in providing larger quantities of this repressive factor and 15 °C higher temperatures, produced biomass similar to that thereby keeping the plant in the vegetative growth stage. of wild type plants cultivated under normal conditions. MB The inhibition of flowering prolongs the vegetative growth, which enables us to control the morphology and thus the Thus, FTs acting as floral inducers are promising candidates for PD Dr. Gundula Noll yield and biomass of the plant. Such optimized tobacco plants breeding programs aiming at adapting various crops to the [email protected] reached heights of around five meters and thus an increase in effects of climate change. For example, it would be interest­ ­biomass of up to 60 percent due to the leaf size alone, further ing to test this breeding strategy in vegetative plants such as ­increased enormously by the formation of up to 10 times more potatoes, sugar beet or lettuce, where carbon and energy leaves. The elucidation of the mode of action of activating­ distribution into the vegetative organs is desirable and a pro- versus repressing FTs now allows us to precisely regulate plant longed vegetative growth phase by modulating the activity of architecture, flowering time and seed quantity and thus the FTs could be beneficial. In the case of potato, research on the yield realized by use of modern breeding methods such as specific functions of the different FTs is of particular interest. In TM CRISPR/Cas. In this way, we achieve economically relevant this plant, tuber formation is also dependent on the availa- and, above all, field applicable breeding objectives. bility of certain FTs and a targeted modulation of FT levels

52 53 SELECTED

PUBLICATIONS

Plant cell packs named cookies

Characterization of protein interactions in living cells

Deciphering the mechanisms of rubber biosynthesis in dandelions

Impact of insect meal on fat metabolism

Novel insights into the mechanism of caspase-6

Bioconcentration studies with the crustacean Hyalella azteca

»5«

In 2019, Fraunhofer IME researchers published about 150 articles in peer-reviewed journals.

55 Dr. Dr.-Ing. Johannes Buyel Plant cell packs in 96-well Dr. Tilo Knape Protein-interaction-dependent Head of Department format. Research fellow FRET signals in living cells. Bioprocess Engineering Translational Drug Validation | Biochemical Pathology

PLANT CELL PACKS NAMED COOKIES CHARACTERIZATION OF PROTEIN INTERAC- TIONS IN LIVING CELLS

»THE NEW TECHNIQUE ENABLES RAPID, REPRODUCIBLE AND PARALLEL »DETAILED KNOWLEDGE ABOUT PROTEIN INTERACTIONS HELPS TO UNDERSTAND SCREENING OF RECOMBINANT PROTEINS« THE CAUSES OF DISEASES AND TO TREAT THEM THERAPEUTICALLY«

Protein expression in plants offers several advantages in terms initial activity tests. The costs are around 25 cents per sample. The detailed identification and characterization of protein-­ of human diseases and to characterize in detail the binding of production costs and safety compared to ­mammalian To date, we have successfully tested the method with a wide protein interactions is of fundamental importance to profile of drugs. cell cultures. However, until now there has been no ­reliable ­variety of plant cells and products: From carrots to tobacco ­investigate the causes and development of diseases, to identify way for plants to test large numbers of different ­product and from antibodies to toxins. But we're moving on. We new molecular and pharmacological targets, to detect subtle TM Translational Medicine and Pharmacology ­candidates, e.g. with regard to their accumulation, at a are currently working to automate all steps of the proto- changes in protein interactions in drug treatment, and to verify ­reasonable cost. col in ­order to fully exploit the potential of the technology. the pharmacological and toxicological potential of new and We are also establishing correlation factors with which we existing drugs. Trümper, V., von Knethen, A., Preuß, A., Ermilov, E., Hack- In the Department Bioprocess Engineering (formerly ­Integrated can ­transfer PCP results to whole plants and thus to many barth, S., Kuchler, L., Gunne, S., Schäfer, A., Bornhütter, T, Production Platforms), we have now developed and ­patented ­hundreds of kilograms of biomass. In order to further minimize the disadvantages of current Vereb, G., Ujlaky-Nagy, L., Brüne, B., Röder, B., Schindler, M., an innovative technology that impressively solves this ­problem: preclinical in vitro test systems such as high costs, low Parnham, M.J., Knape, T. Plant cell packs (PCPs), also known as “cookies“­ due to their MB Molecular Biotechnology ­throughput and limitations in terms of selectivity, specificity Flow cytometry-based FRET identifies binding intensities flat, light form. PCPs are plant cells that we first keep in cell and sensitivity, we have developed a systematically improved, in PPARγ1 protein-protein interactions in living cells (2019) culture and which we then deprive of liquid medium. The innovative, flow cytometry-based Förster Resonance Ener- ­Theranostics, 9(19), 5444-5463. DOI: 10.7150/thno.29367 remaining cake can then be treated with ­Agrobacterium Rademacher, T., Sack, M., Blessing, D., Fischer, R., Holland, T., gy Transfer (FRET) test system for the molecular ­verification ­tumefaciens: A mere drop of the bacterial solution is ­sufficient. Buyel, J. of specific protein-protein interactions. With a special The soil-borne bacterium has the natural ability to ­transfer Plant cell packs: A scalable platform for recombinant pro- ­focus on the human nuclear hormone receptor peroxisome DNA into plant cells and we have modified this DNA to tein production and metabolic engineering (2019) Plant ­proliferator-activated receptor gamma (PPARγ), we were able contain the information for the product candidates we are ­Biotechnology Journal, 17 (8), 1560-1566. DOI: 10.1111/ to demonstrate for the first time that our in vitro test ­system ­interested in. The result of the treatment is the accumulation pbi.13081 provides detailed, reliable and reproducible data for the of the candidates in the plant cells within three to five days. identification and characterization of binding intensity and Our method is several times more efficient than a similar affinity of direct protein-protein interactions from PPARγ with ­treatment of plant cells in liquid culture. Since PCPs can be its co-factors in a high-throughput test system in living cells. cast into various formats, including 96-well plates, we can By improving the sensitivity of our in vitro test system, it can use the method for both screening and scale-up to supply 2be used to identify new therapeutic targets for the treatment

56 57 Eva Niephaus The Russian dandelion, a natural Prof. Dr. Holger Zorn Mealworms are considered as a PhD student rubber source. Head of Department source of high quality protein. Functional and Applied Genomics Food- and Feed Improvement Agents

DECIPHERING THE MECHANISMS OF RUBBER IMPACT OF INSECT MEAL ON FAT BIOSYNTHESIS IN DANDELIONS ­METABOLISM

»ESTABLISHMENT AS A RUBBER CROP REQUIRES FUNDAMENTAL KNOWLEDGE »OUR INVESTIGATIONS SHOW THAT INSECT MEAL HAS BENEFICIAL EFFECTS IN ABOUT THE RUBBER METABOLISM IN DANDELION« THE CASE OF FAT METABOLISM DISORDERS«

The demand for natural rubber is growing steadily: Car tires, ­Alternatively, other secondary plant compounds, whose In our studies we investigated the hypothesis that insect meal ­individual phospholipids can strongly influence membrane rubber gloves and pacifiers are just three examples of about synthesis is closely linked to that of rubber, are increasingly as a protein source has a beneficial effect on fat metabolism. properties (enzyme activities, activities of transport proteins). 40,000 products containing the plant biopolymer. Natural ­formed. As part of our experiments, we were able to show To this end, we conducted two experiments with obese rats, Overall, our investigations show that feeding insect meal to ­rubber can often not be replaced by synthetic, petroleum-­ that these are now increasingly found in the latex particles which are considered a model for obesity and metabolic obese rats has very positive effects on fat metabolism. based polymers due to its unique properties. For this reason, in place of rubber. Extensive proteome analyses of rubber-­ syndrome in humans. Two groups of rats received either the economic importance of alternative sources other than deficient dandelion plants enabled us to derive further casein or insect meal as a protein source. In both experiments, These studies give reason for hope that similar beneficial the rubber tree, as the only commercially used source to ­potential factors, different metabolic pathways associated with we found that rats fed insect meal had drastically reduced ­effects could also occur in overweight persons. Since insect date, is increasing. The development of the Russian ­dandelion rubber ­biosynthesis, as new starting points for future research. cholesterol and triglyceride levels in blood plasma and liver by meal is a complex mixture of different bioactive substances, ­(Taraxacum koksaghyz) into a natural rubber crop has made up to 60 percent. The livers of the rats in the group recei- our current studies focus on identifying the ingredients of considerable progress in recent years. Nevertheless, not ving insect meal were also significantly smaller and already insect meal that are responsible for the beneficial effects. MB Molecular Biotechnology all individual components and metabolic links of rubber externally visibly showed a lower fat content than those of AE Bioresources ­biosynthesis are fully known yet. However, it is crucial to the control groups with casein as a protein source. Extensive BR ­understand these in detail in order to produce plants with a Niephaus, E., Müller, B., Deenen, N., Lassowskat, I., Bonin, investigations using complex analytical methods showed that high production capacity. M., Finkemeier, I., Prüfer, D., Schulze Gronover, C. the reduced cholesterol and triglyceride levels in blood plasma Uncovering mechanisms of rubber biosynthesis in Taraxacum and liver were the result of inhibition of cholesterol and Meyer S, Gessner DK, Wen G, Most E, Liebisch G, Zorn H, As part of our study, we identified a protein (TkCPTL1) that koksaghyz – role of cis-prenyltransferase-like 1 protein (2019) triglyceride synthesis in the liver. The rats fed insect meal also Ringseis R, Eder K. is essential for dandelion rubber biosynthesis. TkCPTL1 forms The Plant Journal, 100 (3), 591-600. DOI: 10.1111/tpj.14471 had lower levels of homocysteine, a substance closely related The antisteatotic and hypolipidemic effect of insect meal in a complex through its interaction with a catalytically ­active to cholesterol metabolism and also considered a risk factor for obese zucker rats is accompanied by profound changes in ­protein. It is located on the surface of particles found in arteriosclerosis (hardening of the blood vessels). We also found hepatic phospholipid and 1-carbon metabolism. Molecular the ­latex of dandelion. There, the complex synthesizes the that insect meal diets lead to changes in the composition of Nutrition & Food Research, 63 (8), e1801305. DOI: 10.1002/ long polymer chains that are stored inside the particles. The cell membranes, with the proportion of certain phospholipids mnfr.201801305 ­targeted reduction of TkCPTL1 gene expression prevents (phosphatidylethanolamine) increasing and the proportion the formation of a functional complex. As the interaction of other phospholipids (phosphatidylcholine) decreasing. partner is missing, the plant can no longer produce rubber. These changes are also very significant, since the contents of

58 59 Dr. Sheraz Gul Docking pose of the allosteric Prof. Dr. Christian Schlechtriem Hyalella azteca, an epibenthic Research fellow inhibitor and caspase-6. Head of the Department amphipod, under the micros- Drug Discovery Bioaccumulation and Animal Metabolism cope.

NOVEL INSIGHTS INTO THE MECHANISM OF BIOCONCENTRATION STUDIES WITH THE CASPASE-6 CRUSTACEAN HYALELLA AZTECA

»A COLLABORATION WITH THE MOST CITED AUTHOR FOR HUNTINGTON’S » HYALELLA AZTECA HAS A HIGH POTENTIAL TO BE USED AS ALTERNATIVE TEST ­DISEASE BRINGS US ONE STEP CLOSER TO DISCOVERING A TREATMENT FOR HD« ORGANISM TO FISH FOR BIOCONCENTRATION STUDIES«

Fraunhofer IME has been collaborating with Dr. ­Michael vitro pharmacology and absorption, distribution, metabolism,­ Bioconcentration factors (BCF) for regulatory purposes are correlation with fish BCF values. Therefore, H. azteca has a ­Hayden of the University of British Columbia who is the ­excretion and toxicity studies and showed to meet industry­ usually determined by fish flow-through tests according to high potential to be used as alternative test organism to fish most cited author in the world for Huntington’s disease. The standard “Lead Compound” criteria. As this is a major­ technical guidance document OECD 305 (OECD 2012). Fish for bioconcentration studies. A protocol for bioconcentration focus of the research project has been to identify inhibitors milestone in the drug discovery value chain, a patent bioconcentration studies are time consuming, expensive, tests with H. azteca under standardized conditions, including of the caspase-6 enzyme which processes huntingtin protein. ­entitled ­“Modulators of Caspase-6” was granted (PCT/ and use many laboratory organisms in the range of 100–200 the flow-through and semi-static test design, has been de- This is considered a crucial event in Huntington’s disease IB2015/000144). Once the intellectual property relating to the ­organisms per study. Alternative methods that may help to veloped as part of project CEFIC-LRI ECO40. ­­pathogenesis. compounds was secured, the research team published a paper reduce the use of fish for BCF testing would therefore be AE During the research project, Fraunhofer IME developed a novel in Cell Chemical Biology which describes in detail the results of of value. Hyalella azteca is an epibenthic amphipod, which BR Applied Ecology assay to measure caspase-6 mediated processing of huntingtin the ­collaboration. is wide­spread in North and Middle America and commonly protein. This assay was successfully miniaturized and screened used for ecotoxicity studies with and without sediment. The against 22,644 compounds, and one specific compound series TM ScreeningPort freshwater amphipods can be easily cultured in the ­laboratory Schlechtriem, C., Kampe, S., Bruckert, H.J., Bischof, I., was shown to inhibit caspase-6 with high efficiency. This initial and are available during the entire year. Due to their high Ebersbach, I., Kosfeld, V., Kotthoff, M., Schäfers, C., L’Haridon, J. exciting result led to a further collaboration between the part- ­reproduction rate and fast growth, experimental organisms Bioconcentration tests with fish and the freshwater amphipod ners in order to progress the most promising compounds in Ehrnhoefer, D.E., Skotte, N.H., Reinshagen, J., Qiu, X., Winds- can be raised within a few weeks to adult size to meet the Hyalella azteca. Are the results predictive of bioconcentration the drug discovery value chain. The research teams performed hügel, B., Jaishankar, P., Ladha, S., Petina, O., Khankischpur, need for a high number of large organisms required for bio- in fish? (2019) Environmental Science and Pollution Research a comprehensive study of the caspase-6 inhibitors and the M., Nguyen, Y.T.N., Caron, N.S., Razeto, A., Meyer Zu Rheda, concentration testing. 26, 1628–1641. DOI: 10.1007/s11356-018-3677-4 most significant finding from this work was the identification M., Deng, Y., Huynh, K.T., Wittig, I., Gribbon, P., Renslo, A.R., In this study, we estimated the bioconcentration potential of of inhibitors which block the interaction between caspase-6 Geffken, D., Gul, S., Hayden, M.R. a wide range of substances in H. azteca to allow a compari- and huntingtin protein. Molecular docking studies suggested Activation of caspase-6 is promoted by a mutant Huntingtin son with fish BCF data described in the literature. Fourteen that the inhibitor binds an allosteric site in the caspase-6 and fragment and blocked by an allosteric inhibitor compound substances of different hydrophobicity (log Kow 2.4–7.6) were this can explain the highly selective nature of the inhibitors. (2019) Cell Chemical Biology 26 (9), 1295-1305. DOI: tested under flowthrough conditions to determine steady state In conclusion, we have identified a compound series with a 10.1016/j.chembiol.2019.07.001 and kinetic bioconcentration factors (BCFss and BCFk). We novel mode of action with high fidelity for caspase-6. The found that bioconcentration studies with the freshwater am- most optimal compounds were evaluated in ­preclinical in phipod2 H. azteca result in BCF estimates, which show a strong

60 61 PEOPLE AND EVENTS

Brief reports Employees, meetings, successes and new perspectives at Fraunhofer IME

»6«

In 2019 533 employees worked at Fraunhofer IME.

63 Catherine Müschen successful in the Immunology Day of Fraunhofer CIMD With insects on patrol - Bees in action as High Performance Center “Networked, Young Research Class drug sniffers Adaptive Production“ well positioned

Catherine Müschen, PhD student at Fraunhofer IME in On June 19, 2019, the first “Immunology Day“ of the Fraun- Could bees in the future support the police in drug On April 16, 2019, the High Performance Center based in ­Aachen, has been participating in the two-year Young hofer Cluster of Excellence Immune-Mediated ­Diseases CIMD ­investigation? A 22-year-old inspector from Cologne dealt Aachen received positive feedback from the five-member ­Research Class program of the Fraunhofer-Gesellschaft since took place in Frankfurt am Main. The field of participants with this question in her bachelor's thesis and attracted a expert committee that the Fraunhofer-Gesellschaft had asked summer 2018. In her team of four, she was happy about consisted of employes from the core institutes of the research lot of attention, both in security circles and in the media. In to evaluate the project: For almost three years, a team of the approval of the “In silico-driven bioprocesses“ research cluster (Fraunhofer IME, ITEM and IZI) and from 38 other February, she was awarded the “Future Prize of Police Work” researchers from the three Aachen-based ­Fraunhofer ­Institutes project, which started on March 1, 2019. The Young Research Fraunhofer institutes. A total of 170 participants ­attended the for her work. IPT, ILT and IME had been working on the development­ Class combines the development of original research ideas event. of a common procedure for processing production data. with networking across hierarchies and disciplines. Scientists The idea is based on the research of the LOEWE Center for The evaluators' positive recommendation launches the who have just completed their doctorate or are in the final During “Immunology Day”, the participants gained insights Insect Biotechnology at the University of Gießen, which has next ­funding phase. Dr. Dr.-Ing. Buyel and his team from phase of their doctorate can take part. into the work of the research cluster. The cluster's scientists been conducting research on bees and their outstanding sense ­Fraunhofer IME are contributing their expertise in the field of presented their scientific projects, invited ­physicians explained of smell for years. ”It is so accurate that it is all about the ”Big Data Analytics in complex production environments“. The key topic in 2018 was “Biological transformation“. In the what their patients desire most (the “medical need”) and ­recognition of individual molecules” explains Prof. Andreas Research Camp, which took place in Waischenfeld in June representatives from the pharmaceutical industry outlined the Vilcinskas, head of the Branch for Bioresources of ­Fraunhofer The three Fraunhofer institutes have successfully fulfilled 2018, the 15 participants worked out project ideas. Catherine requirements and conditions of the market. IME in Gießen. And since bees are able to remember ­these the task of designing an open research platform and test Müschen and colleagues from Fraunhofer Institutes IBP, ITWM odors quickly, they can be conditioned to any odorous environment for industry in which new concepts of ­digitized and IIS developed the idea “In silico-driven bioprocesses“. The Fraunhofer CIMD is dedicated to translational research. It thus ­substance within a few seconds using weak but unpleasant production can be tested and evaluated in a practical manner.­ aim of this project is to accelerate biological drug ­production transfers basic research into application. Fraunhofer CIMD current pulses. Industrial partners including IT system providers, plant and process development using plants as an example. The works in the four areas of health research - Drugs, Diagnostics,­ ­manufacturers and manufacturing companies have joined the team presented this project idea to the President of the Devices and Data, the 4D. These four subject areas are In practice, this technique could be used for example at High Performance Center in an open research community and ­Fraunhofer-Gesellschaft, Prof. Dr.-Ing. Reimund Neugebauer, ­represented by the four professional groups - ­physicians, airports, where a machine sucks the air from the suitcases into ensure additional practical relevance. and the Fraunhofer Think Tank at the project exhibition in ­scientists, engineers and computational experts. The a box of bees. The reaction of the insects can then be used to ­September 2018. Subsequently, the project proposal was ­“Immunology Day” was used to discuss further cooperation­ detect illegal substances in the luggage. Flying missions are In each of the four relevant activities “Profile and prepared and submitted for review. In mid-February 2019, possibilities with a focus on how ideas can be applied cost-­ also possible. While the classic police dogs have to be trained ­Implementation“, “Location and Impact“, “Transfer and the grant was awarded and experimental work at the four effectively and transferred into new treatment options. for months, bees have the additional advantage, apart from Sustainability“ and “Strategy and Perspective“, the evaluators ­Fraunhofer Institutes began on March 1, 2019. the quick conditioning, that they can always be trained for rated the High Performance Center with top grades. The For Catherine Müschen, the “Young Research Class“ is The “Immunology Day“ was a successful kick-off for the new substances and can be used for a longer period of time. Aachen-based institutes received special recognition for their an opportunity to apply for projects and carry them out promotion of networking, collaboration and cooperation They can work through up to 48 hours. The police union (GdP) excellent cooperation with partners from industry, science ­independently. Holding your first funding decision in your opportunities along the 4D within the entire Fraunhofer-­ sees this research as a ”possible revolution for police work”. and politics as well as the high satisfaction of the industrial AE hand is an important moment. The highlight of the project will Gesellschaft. TM BR partners. The evaluators also highlighted the distinct thematic be the presentation at the Fraunhofer Netzwert Symposium focus of the High Performance Center and, associated with 2020 in Munich. MB this, the high visibility as a hot spot and networking hub with outreach beyond the west german region. MB

64 65 3

Equal rights officers at Fraunhofer IME Fraunhofer IME organizes stem cell Learning partnership signed and sealed Federal Environment Minister visits Kids‘ founded network symposium with cooperation partner Lab of the Environmental Specimen Bank

Gender equality, compatibility of family and career, as On the occasion of the visit of the First Mayor of the Free At the end of June, Rita Hündgen, headmistress of the On August, 17-18, 2019, the Federal Ministry for the well as protection against sexual harassment – these are and Hanseatic City of Hamburg Dr. Peter Tschentscher with ­Cusanus-Gymnasium in Erkelenz and Dr. Dr.-Ing. Johannes ­Environment, Nature Conservation and Nuclear Safety held some topics the equal rights officers (German: Beauftragte a business and science delegation to Japan, Fraunhofer IME Buyel, head of department at Fraunhofer IME in Aachen, an open day in Berlin to outline its function. Also present für ­Chancengleichheit, BfC) dedicate themselves to. They and its partner FBRI (Foundation for Biomedical Research and signed a cooperation agreement. After a two-year test phase, was the Kids‘ Lab of the Environmental Specimen Bank, are bound to discretion, so that all who have concerns or Innovation at Kobe) organized a scientific symposium in Kobe, the learning partnership has now been sealed. During the ­supported by Fraunhofer IME. On this occasion, children could ­problems in this regard can address their sorrows to them Japan on August 29, 2019. The symposium on the topic “New course of their school curriculum, pupils can visit Fraunhofer ­experiment with liquid nitrogen at temperatures of minus 196 trustfully. To ensure a policy of equal opportunities and as a opportunities for drug discovery with stem cell technologies”­ IME and will be informed about a “model of the working degrees Celsius, just like real scientists with ­laboratory coat, contact person for the employees each of the Fraunhofer IME was under the patronage of the director of FBRI, the ­immune world in the form of a modern, science oriented research in- gloves and protection goggles. They were able to learn about locations has its own equal opportunities officer and deputy. researcher and Nobel Laureate in Medicine 2018 Prof. Dr. stitution with a highly qualified range of services“. Key topics the different sample types of the Environmental Specimen However, Fraunhofer IME with its many sites provides the ­Tasuku Honjo, and Dr. Peter Tschentscher, a habilitated of the cooperation are “opening of school and teaching“, Bank. Federal Environment Minister Svenja Schulze took the ­opportunity to connect these small teams to a whole network. ­physician. “action orientation“ and “career choice and working world ­opportunity to learn about the Environmental Specimen Bank This chance was taken by the BfC of the institute locations In his welcoming address, Dr. Tschentscher paid special tribute orientation“. As a learning ­partner, Fraunhofer IME offers at the exhibition stand of Fraunhofer IME. Since the year ­Aachen (Greta Nölke and Christiane Fischer), Frankfurt am to the international cooperation between Hamburg research pupils - especially those in the upper secondary school - the 2000, Fraunhofer IME operates the German ­Environmental Main (Carmen Walter and Susanne Schiffmann), Gießen institutions, which is expressed in particular in the close part- opportunity to gain insights into attractive­ professional fields, Specimen Bank as a core element for ­environmental ­(Kirsten Bommersheim and Sabine Schmelzle) and Schmallen­ nership between the Kobe Biomedical Innovation Cluster and training and study courses, which are opened up to them with ­monitoring in Germany on behalf of the Federal ­Ministry berg (Elke Eilebrecht and Jennifer Teigeler). They met for Life Science North. In his keynote, Prof. Dr. Carsten Claussen the completion of the advanced technical college or general for the Environment, Nature Conservation and Nuclear the first time on July 11, 2019 in Gießen in order to found reported on exactly such a cooperative research project, in university entrance qualification. ­ Safety. In the course of this program, Fraunhofer IME also the Fraunhofer IME BfC network. Already during this first which the disease hypothesis, clinical evidence of stem cell In addition to this basic orientation offer, the following ­conducts retrospective monitoring to examine the content of ­meeting, they agreed on topics which will be in the focus of therapy is linked to the Hamburg screening results and his ­activities are planned: Selective activities by Fraunhofer ­currently relevant chemicals in specimens from the Specimen the ­network. stem cell assays. Prof. Dr. Akihiko Taguchi the PI of this project IME in the field of biology; excursions for the pupils of the Bank. By this means, it can be verified whether substance The first initiative was the presentation of a joint poster at the in the field of dementia disease added impressive clinical data. ­advanced biology courses to Fraunhofer IME allowing them ­restrictions by public authorities or voluntary use restrictions All-IME Summer Meeting. On this poster, the BfC introduced Other German speakers included Prof. Dr. Heiner Dobner, to explore the field of research; further training for biology of certain ­substances by the producer, result in a decrease in themselves and provided information about the topic elder- Director of the Heinrich Pette Institute, who explained the teachers on current topics in molecular biology and applied ­concentration of those substances in the environment. The care. In this context, the BfC together with the pme Family potential of human adult stem cells for infection research. Dr. ecology; creation of an information platform on training results of these studies are compiled in reports and published Service can support the employees to organize the care of Peter Fruhstorfer, CEO Eppendorf AG, concluded the ­industrial ­opportunities at Fraunhofer IME and in the various institutions in international journals. Examples of relevant substances relatives. Furthermore, the BfC informed interested employees discussion with the need for standardized, QC-supported of ­Fraunhofer-Gesellschaft. Johannes Buyel is pleased that found are organotin compounds in mussels of the North and about their manifold functions and were available for further ­processes and tools. Two Japanese contributions from the the cooperation will be ­continued: “I am committed to the Baltic Sea, perfluorinated compounds in different organisms questions and discussions. Riken Institute and Kobe University dealt with the use of stem learning partnership, as pupils have few opportunities to gain of the marine food web or Triclosan and Methyltriclosan in AE For the future, the Fraunhofer IME BfC network will ­continue cells for regenerative medicine and demonstrated Japan's insights into the professional life of “research“. Personally, I freshwater fish. BR to work together, because they will achieve more when leading role in stem cells worldwide. TM would have gladly accepted such an offer earlier.“ Obviously, ­working together. there is also interest today as can be seen by the praise of the participants “that was cool“. MB

66 67 Start of the new department After mushroom growing, prior to insect Great success for junior rheumatologist at 60 years of Fraunhofer in Schmallenberg Bioprocess Engineering breeding Frankfurt am Main – globally active, locally rooted

In August 2019, the “Bioprocess Engineering“ depart- The production of protein from insects is on the rise The DGRh Research Initiative 2020, with its idea of Celebration of a success story: on October 29, as the new ment was established in Aachen. The team, headed by ­worldwide. It is considered to be particularly ­sustainable ­person-related support for young physicians in the field center of the institute nears completion, Fraunhofer IME Dr. ­Johannes Buyel, focuses on various aspects of protein ­compared to traditional livestock farming. However, of rheumatology, has announced the two prize winners ­celebrated with 160 guests from science, economy and production from the gene to the finished product. Despite ­sustainability depends to a large extent on the food used ­following a nationwide competitive selection process at this policy the sixtieth anniversary of the Fraunhofer-site in great progress in the production of recombinant proteins, to feed the insects. In the EU there are strict regulations year's Rheumatology Congress in Dresden. One of the prize Schmallenberg-­Grafschaft. As well as an overview of the rele- there are no ­generic ­protocols and process development is ­r­egarding approved food for insects. This is why cereal-­ winners is Dr. Sorwe Mojtahed Poor (2nd from right) from vant past and present research activities in Schmallenberg, a necessary on a ­case-by-case basis. Johannes Buyel, among based food such as chicken or pig food is often used. If the the Rheumatology Department of the University Hospital of look ahead to future research topics was given. Investment of others, relies on the plant system as a production platform insects ­produced in this way are used as animal food, the the Goethe University Frankfurt am Main. The award covers almost 30 ­million euros by the federal government, state and and ­believes that “for some proteins, plants are a good ­sustainability of this “detour“­ is questionable. the funding of her position for two years, thus allowing her institute funds enable continued future research. A new mem- ­alternative to ­established microbial and animal ­systems to devote herself to a patient-oriented research project in ber of the executive board of Faunhofer-­Gesellschaft, Executi- or even the much more efficient produc­tion system“. It is therefore important to use food sources for insect ­cooperation with Fraunhofer IME. The close cooperation ve Vice President Technology Marketing and ­Business Models, ­Contemporary ­protein ­production processes consider from ­breeding that comply with EU requirements but do not between ­Fraunhofer IME and the Goethe University played a Prof. Dr. Ralf B. Wehrsporn, emphasized the ­relevance of the the beginning the ­properties of genes and proteins, the ­compete with traditional farm animal food. Dr. Martin Rühl major role in the selection of Dr. Poor, as this ensures that the Schmallenberg site as a nucleus of Fraunhofer ­health research. quantity and quality of the products required, downstream from the Bioresources Division of the Fraunhofer Institute for physician is ­embedded in a competent translational research In their official address, state commissioner Dr. Karl Schneider ­processing issues, ­regulatory requirements and intellectual Molecular Biology and Applied Ecology IME in Gießen, ­sees environment. and parliamentary state secretary of the Ministry for Culture property issues that might arise. Only then can the most potential in the use of harvested fungal ­substrate from edible and Science of the state of North Rhine-­Westphalia (NRW), ­appropriate production­ strategy be selected. The department mushroom cultivation. This extension of the value chain could Dr. Poor has already participated in a PhD program at Klaus Kaiser, highlighted the relevance as an ­employer in the has established an automated and integrated platform for open up a previously unused straw- and wood-based by-­ ­Fraunhofer IME and successfully combined laboratory research region and as an important part in the research landscape of the screening of gene variants. This allows ­translation from product stream for the production of valuable animal protein. with clinical questions. Within the scope of the awarded DGRh NRW. Environmental spokesperson of the European People’s the gene to protein production­ on a pilot scale in less than funding, Dr. Poor will focus on the research of cardiovascular Party (EPP) in the European Parliament and head of CDU-­ four weeks and ­combines ­parallel chromatographic purifi- After the first promising laboratory-scale experiments concomitant diseases in rheumatic disorders and in particular Europe group, MEP Dr. Peter Liese (picture above), praised in cation and protein analysis. The ­experiments are typically ­developed by Fabiola Neitzel as part of her master's thesis at on valid, early detection methods of such manifestations. his speech the important contribution of Fraunhofer IME to ­based on a design-of-experiments strategy. This strategy the Bioresources department of Fraunhofer IME in ­Gießen, The aim is not only the timely detection of such concomitant the protection of the environment and consumers and asked ­provides comprehensive­ information and descriptive models ­Neitzel and Dr. Rühl have now started an industrial pilot diseases of the cardiovascular system, but also their successful for participation in the EU ­research ­program Horizon ­Europe, for the complex influences of different process ­parameters, project with the Swiss Mushroom Producers Association (VSP). treatment with intensified anti-rheumatic therapy in order to mission against cancer. Prof. Dr. Adolf Eisenträger, head enabling rapid process optimization. The approach is The insect larvae, which are cultivated on a worn fungal further reduce the mortality of patients with inflammatory of the division ­Pharmaceuticals, Chemicals and ­Substance ­complemented by mechanistic models describing expression ­substrate, could in future contribute to the feed supply of fish rheumatic diseases. This project is again being carried out in Analysis at the German Environment Agency (UBA) outlined AE and chromatographic­ purification, allowing the investigation and poultry farms with regional protein sources. BR close cooperation between Fraunhofer IME in Frankfurt am the close ­cooperation between UBA and Fraunhofer IME the of many conditions in silico. By bundling these expertises, the Main and the University Hospital of the Goethe University. TM Environmental Specimen Bank and gave an example of the team around Mr. Buyel offers clients the possibility­ to bring development of a guideline. Guests also visited the developing AE their product to market faster. MB laboratory building. BR

68 69 Kenyan DAAD-delegation visits Starting signal for the trilateral Urban TaraxaGum - the bicycle tire made Early detection of potential immuno- Fraunhofer IME in Schmallenberg cooperation project inCELLphosTAG of dandelion toxicity of immunomodulatory drugs

A high-level delegation from Kenya visited Germany to With the inCELLphosTAG project, Fraunhofer IME, together After several years of intensive joint development work with For many decades pharmaceuticals entering the market either ­become familiar with the German science system and to with the University of Hamburg and PerkinElmer, has won Fraunhofer IME, Continental Reifen Deutschland GmbH have been derived from traditional, mainly plant-related discuss possibilities to cooperate. Among this ­delegation funding under the new Fraunhofer-DFG cooperation program. ­presented the Urban TARAXAGUM® in 2019, the first serially compounds or consist of small molecular chemicals. In recent were representatives of the National Assembly, of the produced bicycle tire made of dandelion rubber. The ­natural years, there has been a marked upswing in the development State ­Department for Agricultural Research, of the Kenya In 2018, the Fraunhofer-Gesellschaft and the Deutsche rubber is obtained from roots of the Russian dandelion of biopharmaceuticals, initially therapeutic antibodies, but ­Agricultural and Livestock Research Organization, of the ­Forschungsgemeinschaft (DFG, German Research ­Foundation) ­Taraxacum koksaghyz. Like the tropical rubber tree, the latex also cellular therapies, nucleic acids and genes. Such agents ­National Treasury, of the National Research Fund, of Kenya launched a cooperation program to effectively transfer of these plants contains large quantities of high-molecular-­ not only require different, more complex and often very costly ­Private Sector Alliance KEPSA, of the University of Eldoret and basic research into applications. It is based on results from weight ­rubber. Prof. Dr. Dirk Prüfer and his team have paved production processes and adapted strategies for testing of of the presidential office. Agricultural topics were the focal DFG-­funded projects that are to be further developed in the way for this development in the cycling capital Münster. experimental and clinical efficacy, they also raise challenges to point of the visit. At first, the delegation visited the German ­cooperation with Fraunhofer working groups and an ­industrial Together with the WWU Münster, they researched in particular the testing and prediction of potential adverse effects on the Academic Exchange Service (DAAD) as the host organization application partner. It offers scientists in basic research the rubber biosynthesis in dandelions. immune system and other organs and tissues. and the German Research Foundation (DFG) in Bonn. The the ­opportunity to further develop their inventions into next morning, a visit to the Center for Development Research market­able products and services, as well as companies the Tests conducted by the cooperation partner Continental have To address this issue, the European Innovative Medicines University of Bonn was scheduled. Afterwards the delegation ­opportunity to participate in technological developments at an shown that not only the car tires but also the bicycle tires are Initiative (IMI) announced a call for proposals to develop new traveled to Schmallenberg, where Fraunhofer-Gesellschaft early stage. roadworthy in every respect. The first limited edition of the approaches to non-clinical predictive testing for immuno­ and Fraunhofer IME with its competences in substance ­folding tire was quickly sold out, but is now available again. toxicity. The winning consortium, led by several Fraunhofer risk ­assessment for the protection of the environment and The trilateral cooperation project inCELLphosTAG aims at The dandelion for this tire is grown in Mecklenburg-Vor- ­institutes, Fraunhofer IME among them and including about consumers were presented by the acting institute director developing an assay technology that enables investigation of pommern. The tires are manufactured in Korbach, Hessen. 25 academic and industrial partner institutes from across the Prof. Dr. Schäfers. Furthermore, DAAD-scholarship holder of important cellular processes and drug targets in relevant cell Due to the much shorter distances between the cultivation EU, is entitled “Immune Safety Avatar: nonclinical ­mimicking the sub-Saharan-Africa program Steve Ayobahan highlighted systems. It does not use radioactively labelled reagents, which areas ­located in Germany and the German or European tyre of the immune system effects of ­immunomodulatory possibilities of the development and application of methods cause health and ecological problems and whose application ­factories, the effort for logistics and transport is drastically ­therapies“ or imSAVAR. Nearly half of the partners are to identify endocrine effects. After the presentation of the is subject to strict regulation. Moreover, these reagents are reduced and resources can be used more sustainably. MB ­pharmaceutical companies who guide the planned ­research German Environmental Specimen Bank by Sonja Uhlig, the not able to cross intact cell membranes and are therefore not to ensure that real world drug development issues are ­delegation travelled to Braunschweig. Here, the delegation suitable for cell-based high-throughput investigations of the ­investigated. imSAVAR was officially approved by IMI in visited the Johann Heinrich von Thünen Institute, Federal major enzyme classes, such as G-protein coupled receptors ­September 2019 and initiated in December 2019. ­Research Institute for Rural Areas, Forestry and Fisheries as (GPCRs) and protein kinases (PKs). Fraunhofer IME will be contributing to several work well as the Leibniz Institute DSMZ-German Collection of ­packages, including the development of novel test models, Microorganisms and Cell Cultures GmbH. During the last days During the 2019-2022 project period, we plan to convert the new ­biomarkers and the establishment of guidelines for of their visit to Germany the delegation spent time in Berlin novel technology into commercial “ready to use“ kit formats. such non-clinical testing. The aim is to define new Adverse and visited the Federal Ministry of Food and Agriculture and This will enable the technology to be widely used and thus ­Outcome Pathways (AOPs) to assist in the future predictive at the German Federal Institute for Risk Assessment (BfR) as advance both basic research and industrial drug research. TM testing of novel immunomodulatory drugs. TM well as the International Green Week. Lastly, the delegation visited the Albrecht Daniel Thaer-Institute of Agricultural and AE Horticultural Sciences of the Humboldt-University. BR

70 71 "Planet Wissen" with Prof. Andreas Ninth PhD Conference in Aachen “Jugend Forscht“ of secondary school Fraunhofer IME and Center for Hybrid Vilcinskas Lennestadt visits Fraunhofer IME Nanostructures create nano-bio devices

Andreas Vilcinskas is Professor of Applied Entomology at the In the doctoral program at Fraunhofer IME in Aachen, the Twenty-seven pupils of the young scientists contest “Jugend­ The Center for Hybrid Nanostructures (CHyN), part of the University of Gießen and Head of the Branch for Bioresources PhD conference is a permanent feature since many years. The Forscht” of the secondary school Lennestadt (“Gymnasium­ der Institute of Nanostructure- and Solid State Physics of the of Fraunhofer IME. On October 9, he was a studio guest at aim is the interdepartmental exchange of knowledge and Stadt Lennestadt, GymSL”) came face-to-face with science. University of Hamburg, is neighbouring the facilities of the "Planet Wissen", where this time everything was dealing with ideas as well as the optimization and consolidation of the PhD Not only did they learn at Fraunhofer IME how Fraunhofer-­ Deutsche Elektronen-Synchrotron (DESY) - and is an integral the fascinating world of insects. ­students' presentation skills. At the end of November the ­ninth Gesellschaft is organized in order to conduct applied research part of the steadily growing Science City Bahrenfeld which PhD Conference took place in Aachen. This year, ­organized but they also had a deep insight into the scientists’ work on aims at hosting all natural science institutions in Hamburg by The lack of habitat and the massive use of environmental by the PhD students themselves, we ­experienced a day full of site. Prof. Dr. Christoph Schäfers, ­acting director of ­Fraunhofer 2025, thereby creating synergistic effects between scientific toxins are causing more and more species to be threatened by exciting lectures and poster contributions. For the first time, IME, committed a whole ­morning to the 13- to 17-­year-old disciplines and basic and applied research. extinction. However, insects have much to offer. Whether as we invited bachelor and master students who for example students. After visiting the ­Environmental ­Specimen Bank the a source for food, as pollinators, or in the removal of carrion, are writing their theses here in Aachen to present a poster. students discussed with Professor ­Schäfers their own ­research The team of Prof. Dr. Robert Blick (CHyN) is focusing on excrement and dead wood, "we depend on them in many For all of them this was the first opportunity to present their projects, which they conduct at the GymSL and received the fabrication and application of hybrid nanostructures for ways. We cannot exist without them," Prof. Vilcinskas points own scientific work to an expert audience. Accordingly, the valuable tips first hand. Which organisms should be­considered ­integrated nano-bio devices. For the first time now, Jann out, because "all habitats on land are dependent on insects in poster sessions were full of interest and willingness to explain for a specific research question? How do you change ­Harberts and Dr. Robert Zierold of CHyN have generated one way or another, without them we can not exist at all". and discuss. In the lectures on topics ranging from ­metabolic ­conditions of an experiment systematically? The participants specialized needle-shaped nanowires which were coated ­engineering of microorganisms to plants as ­production came to Fraunhofer IME with fascinating research questions. with human neurons differentiated from pluripotent stem Thanks to their fantastic nature and abilities, insects ­populate ­systems and bioprocess development, the doctoral candidates Some investigated how the leftovers of disposed cigarettes cells, generated by Fraunhofer IME (Undine Haferkamp and almost all habitats on earth. In the future, we humans could presented their latest results. In the lively ­discussions, they affect the environment, others ­explored the ­consequences Dr. Ole Pless). These neurons were well integrated, formed also benefit from the many survival strategies they have received valuable tips and suggestions for their research. for animals and plants of ­exposure to microplastics. Younger tight interactions with nanowires of different material, ­developed. Whether as suppliers of antibiotics, in biological pupils try to replace plastic with easily ­degradable substances, size and ­patterning, and showed similar functionalities as crop protection or as a future important source of protein for At the staff meeting in early December, acting director of the for instance in dishes, and test different materials. “It is great ­neurons in the human brain, even after weeks of culture. mankind. Prof. Vilcinskas sees great potential in the young institute, Prof. Stefan Schillberg, presented this year's awards. to get support from Fraunhofer IME in our projects when there This nanowire set-up allows for the integration of multiple field of research known as "yellow biotechnology". Parallel The independent jury selected Patrick Kottenhahn from the are hurdles to overcome”, a student said after the visit. GymSL modes of ­interaction with neurons in a single device and to the research at the Center for Insect Biotechnology, the Department of Industrial Biotechnology as ­“Newcomer“ of the is a member of the national Excellence-Network of schools enables ­bidirectional communication with neural circuits world's first international master's degree course in insect year with his presentation ­“Characterization and ­optimization MINT-EC and is particularly focused on supporting explorative with ­enhanced spatiotemporal precision. This combination of AE ­biotechnology and bioresources was established at Justus of 1-hexanol production in CO-utilizing ­Clostridia“. He learning. BR ­technologies not only facilitates a greater understanding of Liebig University in Gießen in 2016. "Learning from insects ­received a textbook of his choice as the prize. From the the brain in the context of health and disease, but as well aim means learning to win," is the motto of Andreas Vilcinskas. group of “Professionals“, the jury awarded a prize to the at impacting the development of novel therapies for neuro­ AE BR ­presentation “Chromatographic Model Calibration“ by Ronald logical, neuro-­immune and neuroendocrine conditions. TM Jäpel from the Department of Bioprocess Engineering. He approached the challenge of how chromatography can be modelled in a very vivid way. He will use his prize money to attend a conference. MB

72 73 FACTS 2019

Publications

Patents

Bachelor’s, Master’s, State Examination and Doctoral Theses

Networks in science and industry

75 PUBLICATIONS

MB Molecular Biotechnology

AE BR Applied Ecology and Bioresources

TM Translational Medicine

77 PUBLICATIONS

Molecular Biotechnology Hussain, A.F., Heppenstall, P.A., Kampmeier, F., Meinhold-Heerlein, I., Barth, S. One-step site-specific antibody fragment auto-conjugation using SNAP-tag technology (2019) Nature Protocols, 14, 3101- A - E 3125. DOI: 10.1038/s41596-019-0214-y

Achtsnicht, S., Neuendorf, C., Faßbender, T., Nölke, G., Offenhäusser, Jansing, J., Buyel, J.F. A., Krause, H.-J., Schröper, F. The correlation between DsRed mRNA levels and transient Sensitive and rapid detection of cholera toxin subunit B using DsRed protein expression in plants depends on leaf age and magnetic frequency mixing detection (2019) PLoS ONE, 14 (7), the 5' untranslated region (2019) Biotechnology Journal, 14 (3), e0219356. DOI: 10.1371/journal.pone.0219356 e1800075. DOI: 10.1002/biot.201800075

Achtsnicht, S., Tödter, J., Niehues, J., Telöken, M., Offenhäusser, A., Jansing, J., Schiermeyer, A., Schillberg, S., Fischer, R., Bortesi, L. Krause, H.-J., Schröper, F. Genome editing in agriculture: Technical and practical 3D printed modular immunofiltration columns for frequency ­consider­ations (2019) International Journal of Molecular Sciences, mixing-based multiplex magnetic immunodetection (2019) 20 (12), e2888. DOI: 10.3390/ijms20122888 ­Sensors, 19 (1), e148. DOI: 10.3390/s19010148 Kern, K., Havenith, H., Delaroque, N., Rautenberger, P., Lehmann, J., Arcalis, E., Ibl, V., Hilscher, J., Rademacher, T., Avesani, L., Morandini, Fischer, M., Spiegel, H., Schillberg, S., Ehrentreich-Foerster, E., Aurich, F., Bortesi, L., Pezzotti, M., Vitale, A., Pum, D., De Meyer, T., Depicker, S., Treudler, R., Szardenings, M. A., Stoger, E. The immunome of soy bean allergy: Comprehensive Russell-like bodies in plant seeds share common features ­identifi­cation and characterization of epitopes (2019) Clinical with prolamin bodies and occur upon recombinant protein and Experi­mental Allergy, 49 (2), 239-251. DOI: 10.1111/cea.13285 ­production (2019) Frontiers in Plant Science, 10, e777. DOI: 10.3389/ Niephaus, E., Müller, B., van Deenen, N., Lassowskat, I., Bonin, M., The enzymes OSC1 and CYP716A263 produce a high variety fpls.2019.00777 Knödler, M., Rühl, C., Emonts, J., Buyel, J. F. Finkemeier, I., Prüfer, D., Schulze Gronover, C. of triterpenoids in the latex of Taraxacum koksaghyz (2019) Seasonal weather changes affect the yield and quality of Uncovering mechanisms of rubber biosynthesis in Taraxacum ­Scientific Reports, 9 (1), 5942. 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Schäfers, C., Licht, O., Bitsch, A. mushroom Cyclocybe aegerita (2019) Beilstein Journal of Organic Dressman, J.B., Schäfer, K., Hutchins, P., Klumpp, L., Mann, J., Nicolai, Endokrin wirksame Umweltchemikalien in Lebensmitteln (2019) Chemistry, 15, 1000-1007. DOI: 10.3762/bjoc.15.98 Translational Medicine J., Ojala, K., Patel, S., Powell, S., Rosenblatt, K., Tomaszewska, I., Deutsche Zeitschrift für klinische Forschung 23/3, 38-45 Williams, J., Augustijns, P. Tonk, M., Pierrot, C., Cabezas-Cruz, A., Rahnamaeian, M., Khalife, J., Biorelevant dissolution testing of a weak base: Interlaboratory Schillo, D., Wipfler, B., Undap, N., Papu, A., Böhringer, N., Eisenbarth, Vilcinskas, A. reproducibility and investigation of parameters controlling in J.H., Kaligis, F., Bara, R., Schäberle, T.F., König, G.M., Wägele, H. 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99 PATENTS

Patent applications Patents issued

Cienciala, Sylvia; Schneider, Nadine; Xu, Bingze; Holmdahl, Rikard; Müller, Boje; Prüfer, Dirk; Schulze Gronover, Christian; Benninghaus, Boes, Alexander; Spiegel, Holger; Edgü, Güven; Beiss, Veronique; Müller, Boje; Prüfer, Dirk; Fischer, Rainer Burkhardt, Harald Vincent Alexander; Epping, Janina Sack, Markus; Reimann, Andreas; Fischer Rainer Artificial forisome body with SEO-F fusion proteins, plant or Production of galactosylated MHC II / CII peptide complexes Verfahren zur Trennung von Polyisopren und anderen apolaren Novel vaccines against apicomplexan pathoges yeast cells comprising vectors which code for these proteins, as EP 19191094.2 Wertstoffen aus pflanzlichen Rohstoffen JP 6461100 B2 well as vectors which code for SEO-F fusion proteins DE 10 2019 133 785.2 US 10,442,840 B2 Do, Nhu Nguyen; Urbonaviciute, Vilma; Cienciala, Sylvia; Holmdahl, Brenneis, Christian; Geisslinger, Gerd; Parnham, Michael John; Rikard; Burkhardt, Harald Schetelig, Marc; Schwirz, Jonas; Yan, Ying; Wichmann, Hendrik ­Scholich, Klaus; Sisignano, Marco; Zinn, Sebastian Rademacher, Thomas HLA-DR /C II peptide complexes with chondroitin-binding Multiprotein expression systems for pest control CYP2J2 antagonists in the treatment of pain Method for the generation and cultivation of a plant cell pack ­peptide (His-tag) for treating arthritis PCT/EP2019/082152; EP18208613.2 EP 3 180 028 A1 (AT, CH, DE, ES, FR, GB, IT, NL, SE); ES 2730050T3 IL 232613A EP 19191077.7 Schiermeyer, Andreas; Ainley, Michael William; Corbin, David; Folkerts, Christen, Urs; Lasch, Stanley; Parnham, Michael John Spiegel, Holger; Boes, Alexander; Edgü, Güven; Beiss, Veronique; Kern, Kai-Uwe Otto Combination therapy for the treatment of autoimmune Sack, Markus; Reimann, Andreas; Fischer, Rainer Bromhexine for the treatment of pain Cultured plant cell lines for DNA targeting ­diseases Three-component-multistage malaria vaccine EP 18729456.6; PCT/US2018/065646 US 62/793,234 CN 106459971 B; JP 6485970 B2; US 20,190,351,056 A1 US 10,213,501 B2

Längle, Thomas; Seiffer, Dirk; Vogel, Simon; Reimann, Andreas Vilcinskas, Andreas; Knorr, Eileen; Narva, Kenneth E.; Gandra, Commandeur, Ulrich; Dickmeis, Christina; Fischer, Rainer Vilcinskas, Andreas; Pöppel, Anne-Kathrin; Wiesner, Jochen Light harvest - Disruptives Hybridbeleuchtungssystem für die Premchand; Geng, Chaoxian; Frey, Meghan; Young, Catherine; Kits comprising plus-sense single stranded RNA viral vectors Polypeptides against plant-pathogenic fungi energieoptimierte Pflanzenproduktion von Morgen ­Balachandran, Abhilash; Fischer, Rainer and methods for producing polypeptides using the kits CN 105102476 B; IDP 00201504871; US 10,266,842 B2 DE 10 2019 209 916.5 Structure specific recognition Protein 1 (ssrp1) nucleic acid EP 2 976 428 B1 (DE, FR, GB, NL); US 10,190,128 B2 ­molecules to control insect pests Weigert, Andreas; Mora, Javier; Brüne, Bernhard; Dillmann, Christina; Müller, Boje; Prüfer, Dirk; Schulze Gronover, Christian EP 18801372.6; PCT/US2018/033296 Fendel, Rolf; Kapelski, Stephanie; Barth, Stefan; Fischer, Rainer; Parnham, Michael John; Geisslinger, Gerd; Rotierend antreibbare Mahlkörpermühle zur Gewinnung von ­Reimann, Andreas N-terminally truncated interleukin-38 Polyisopren und/oder anderen apolaren Wertstoffen Vilcinskas, Andreas; Skaljac, Marisa; Kirfel, Phillipp Peter Anti-parasitic complexes EP 3 194 431 B1 (AT, CH, DE, ES, FR, GB, IT, NL, SE) DE 10 2019 133 787.9 p300/CBP (CRFB-binding protein) nucleic acid molecules to US 10,344,082 B2 control aphids EP 19209940.6 Harig, Lena; Prüfer, Dirk; Fischer, Rainer Nucleic acid sequences and peptides/proteins of the FT ­family providing flower-repressing properties in tobacco and ­transgenic plants transformed therewith EP 2 647 646 B1

Jennewein, Stefan; Engels, Benedikt Melleolide-biosynthesis gene cluster and its application EP 3 092 307 B1 (CH, DE, ES, FR, GB, IE, IT, NL, SE)

Kirchhoff, Janina; Schillberg, Stefan; Schiermeyer, Andreas; Schinkel, Helga; Fischer, Rainer Method for the generation of a monoclonal plant cell line EP 2 717 676 B1, 602011055345.3 (DE)

Narva, Kenneth E.; Worden, Sarah E., Frey, Meghan L.; Rangasamy, Murugesan; Arora, Kanika; Veeramani, Balaji; Gandra, Premchand; Vilcinskas, Andreas; Knorr, Eileen; Dre4nucleic acid molecules that confer resistance to ­coleopteran pests US 10,435,687 B2

100 101 Bachelor’s, Master’s, State Examination and Doctoral Theses

103 BACHELOR’S, MASTER’S, STATE EXAMINATION AND DOCTORAL ­THESES

Bachelor’s, Master’s, State Examination Doctoral Theses Kramer, Jan Sebastian Tarighi, Neda and Doctoral Theses Biochemische und biophysikalische Untersuchungen der lösli- Role of the thromboxane A2 receptor (TP) in peripheral neurons chen Epoxidhydrolase und Protein-Arginin-Methyltransferase 6 in models for acute inflammation Bröker, Jan-Niklas Johann Wolfgang Goethe-Universität Frankfurt am Main Johann Wolfgang Goethe-Universität Frankfurt am Main Functional characterization of enzymes involved in ­Taraxacum koksaghyz isoprenoid synthesis by metabolic pathway Kriebs, Katrin Treutlein, Elsa-Marie ­engineering in Saccharomyces cerevisiae Analysis of the genetic basis, localization and function of PP1 Die Rolle des Prostaglandin E2 bei peripherer Nervenverletzung Westfälische Wilhelms-Universität Münster homologs in Cucumis sativus Johann Wolfgang Goethe-Universität Frankfurt am Main Westfälische Wilhelms-Universität Münster Fracowiak, Jochen Toewe, Andy 26 Etablierung eines funktionalen (Meta-)Genomansatzes zur Kurz, Jennifer Entwicklung einer chiralen Quantifizierungsmethode für ent- ­Identifizierung von Klonen mit antibakterieller Aktivität The role of ceramide synthase 2 and 6 in the pathogenesis of zündungsauflösende Lipidmediatoren in biologischen Matrices Justus-Liebig-Universität Gießen multiple sclerosis mittels Hochleistungsflüssigkeitschromatographie gekoppelt PhD Johann Wolfgang Goethe-Universität Frankfurt am Main mit Tandemmassenspektrometrie 4833 Frank, Ann-Christin Johann Wolfgang Goethe-Universität Frankfurt am Main MicroRNA-375 as novel modulator of macrophage migration in Leber, Jasmin 24 * the breast cancer microenvironment Investigation on the scale-up strategy and harvest for human Visser, Franziska MSc Johann Wolfgang Goethe-Universität Frankfurt am Main mesenchymal stromal cell production in a dynamic bioreactor Molecular and structural characterization of forisome subunits BSc system - Influences of medium, microcarrier choice and new with respect to the development of artificial forisome-based Göckener, Bernd harvest enzymes on the cell quality applications Untersuchung von Pestizidabbauprodukten während der Justus-Liebig-Universität Gießen Theses with the experimental part carried out at Fraunhofer Westfälische Wilhelms-Universität Münster ­Lebensmittelverarbeitung IME (* including 2 state examination theses). Bergische Universität Wuppertal Nothnagel, Lisa Wasmuth, Claus Entwicklung patientengerechter Arzneistoffformulierungen von Silbernanopartikel und Silbernitrat in naturnahen Gewässern Heise, Philipp R-Flurbiprofen zur Therapie der Multiplen Sklerose Westfälische Wilhelms-Universität Münster The microbiome of the burying beetle Nicrophorus ­vespilloides Johann Wolfgang Goethe-Universität Frankfurt am Main as an untapped source for the screening of bioactive small Zimmer, Béla molecules Rosenberger, Julian (geb. Thinnes) The oxidized linoleic acid metabolite 12,13-DiHOME mediates Justus-Liebig-Universität Gießen Rationales Design von Entscheidungsbäumen für die pharma- thermal hyperalgesia during inflammatory pain zeutisch-technologische Entwicklung Johann Wolfgang Goethe-Universität Frankfurt am Main Hoffmann, Daniel Johann Wolfgang Goethe-Universität Frankfurt am Main Produktion des Insektenmetalloprotease Inhibitors in Zitzmann, Jan ­Escherichia coli - Neuartige Plattformtechnologie für die Schäfer, Stefan Martin Gastón Helmut Jonas Prozessintensivierung für die Produktion von antimikrobiellen ­Inclusion body-basierte Produktaufarbeitung Charakterisierung der lipidvermittelten G2A-Aktivierung bei Peptiden mit stabil transfizierten Drosophila melanogaster Justus-Liebig-Universität Gießen entzündlichen Schmerzen S2-Zelllinien Johann Wolfgang Goethe-Universität Frankfurt am Main Justus-Liebig-Universität Gießen Janas, Christine Entwicklung einer Apparatur zur in vitro Testung der Shrestha, Prasit ­Wirkstofffreisetzung aus kolloidalen Arzneistoffträgern Biodegradation testing of hydrophobic and volatile organic Johann Wolfgang Goethe-Universität Frankfurt am Main chemicals Technical University of Denmark Janczi, Thomasz ADAM15 in apoptosis resistance of synovial fibroblasts: Conver- Sprick, Gundula ting Fas/CD95 death signals into the acvtivation of prosurvival Transduktion humaner mesenchymaler Stromazellen mit rekom- pathways by calmoduin recruitment binanten Baculoviren Johann Wolfgang Goethe-Universität Frankfurt am Main Justus-Liebig-Universität Gießen

Kieselmann, Christopher Susen, Rosa Martha Entwicklung und Charakterisierung von Trägersystemen zur Macrophage HIF-2α regulates tumor-suppressive Spint1 in the dermalen Immuntherapie mit Hymenopterenallergenen tumor microenvironment Justus-Liebig-Universität Gießen Johann Wolfgang Goethe-Universität Frankfurt am Main

104 105 NETWORKS IN SCIENCE AND INDUSTRY

107 NETWORKS IN SCIENCE AND INDUSTRY

Networks in Science and Industry Associate Professor at the School of Chemistry at Monash University, Dr. Martin Müller holds lectures about modelling the environmental Dr. Matthias Wacker is Associate Professor in the department of ­Melbourne, Australia. fate of chemicals (QSAR) at RWTH Aachen. Pharmacy of the National University of Singapore and lectures in Phar- macy and Pharmaceutical Sciences. Prof. Dr. Harald Burkhart is Head of the Division of Rheumatology Prof. Dr. Michael Parnham is Professor of Pharmacology and at the Goethe University Hospital Frankfurt am Main and Professor of Toxicology in the Faculty of Biochemistry, Chemistry and Pharmacy Dr. Carmen Walter holds seminars at the Goethe University Hospital Internal Medicine/Rheumatology at the Goethe University Frankfurt at Goethe University Frankfurt. He offers the module ­Pharmaceutical Frankfurt am Main. am Main. Research and Development of the Master of Pharma Business International activities and cooperations with ­Administration (MPBA) of the Goethe Business School. Dr. Björn Windshügel holds lectures at the Jacobs University Bremen. industry Dr. Dr.-Ing. Johannes F. Buyel holds lectures in the master ­program “Molecular and Applied Biotechnology“ at the RWTH Aachen Dr. Ole Pless, Dr. Bernhard Elilinger and Prof. Dr. Carsten Prof. Dr. Holger Zorn is Professor of Food Chemistry and Food ­Claussen hold lectures, seminars and internships at the Faculty of ­Biotechnology and Managing Director of the Institute of Food Fraunhofer IME cooperates with many international research partners ­University. Medicine of the University Hamburg (UKE). ­Chemistry and Food Biotechnology at the Justus Liebig University of and remains in close contact with universities and other research Gießen. organizations. The aim is to recognize trends and developments as Prof. Dr. Carsten Claussen is Honorary Professor for Information Dr. Ole Pless holds seminars at the Goethe University Hospital they emerge, and to develop and implement novel research strategies Systems at the Heinz-Nixdorf Institute of the University of Paderborn. ­Frankfurt am Main. and technologies. In 2019, Fraunhofer IME cooperated with around 100 national and international industrial clients and carried out Prof. Dr.-Ing. Peter Czermak is Professor of Bioprocess Engineering Prof. Dr. Dirk Prüfer is Professor of for Molecular Plant Biotechnology Memberships of Editorial Boards ­confidential projects for several international industrial associations and Pharmazeutical Technology and Managing Director of the Institute of Bioprocess Engineering and Pharmazeutical Technology - IBPT at the at the University of Münster. and Committees Technical University of Central Hessen. Prof. Dr. Till Schäberle is Professor of Natural Product Research Prof. Dr. Jennifer Dressman is Professor of Pharmaceutical with a focus on insect biotechnology at the Justus Liebig University of Scientific Journals Cooperation with universities ­Technology in the Department of Biochemistry, Chemistry and Gießen. ­Pharmacy at the Goethe University Frankfurt am Main. Clinical Trials in Degenerative Diseases (CTDD) Fraunhofer IME has close ties with the Institute of Plant Biology Prof. Dr. Christoph Schäfers holds an Extraordinary Professorship for Editorial Board: Dr. Stephanie Dauth and Biotechnology, the Institute for Evolution and Biodiversity and Dr. Jürgen Drossard holds lectures in the master program “Molecular Eco (system) toxicology at the University of Münster. the ­Institute for Molecular Microbiology and Biotechnology at the and Applied Biotechnology“ at the RWTH Aachen University. Current Research in Drug ­Discovery, Elsevier University of Münster. There is also close cooperation with the Prof. Dr. Marc F. Schetelig is Professor for Insect Biotechnology in Editorial Board: Dr. Sheraz Gul Institute for Insect Biotechnology at the Justus Liebig University in Dr. Bernhard Ellinger holds seminars and internships in the model Plant Protection at the Justus Liebig University Gießen. Gießen, the Institute for Clinical Pharmacology, the Institute for course in Medicine at the University Medical Center Hamburg-­ Dissolution Technologies Pathobiochemistry, the Institute for Pharmaceutical Chemistry and Eppendorf. Dr. Andreas Schiermeyer and Holger Spiegel provide lectures on Editorial Board: Prof. Dr. Jennifer Dressman the Institute for Pharmaceutical Technology, and several clinics, at the Plant Biotechnology at the FH Aachen, University of Applied Sciences. Johann Wolfgang Goethe University in Frankfurt am Main and the Dr. Andreas Ernst holds seminars at the Goethe University Hospital Drug Target Review, Russell Publishing Ltd. RWTH Aachen University. Fraunhofer IME also collaborates with the Frankfurt am Main. PD Dr. Susanne Schiffmann holds seminars at the Goethe University Scientific Contributing Editor: Dr. Sheraz Gul Aachen-Maastricht Institute for Biobased Materials (AMIBM) at the Hospital Frankfurt am Main. University of Maastricht, the Institute for Biology V (Environmental Prof. Dr. Dr. Gerd Geißlinger is Professor and Director of the Environmental Sciences Europe, Springer Research) at RWTH Aachen University, the Institute for Biology at the ­Institute for Clinical Pharmacology of the University Medical Center Prof. Dr. Stefan Schillberg is Honorary Professor at the Justus Liebig Advisory Board: Dr. Kerstin Hund-Rinke University of Siegen, the Center for Fish and Wildlife Medicine at the Frankfurt am Main. He lectures in clinical pharmacology and therapy University Gießen. University of Bern and the School of Chemistry at Monash University for medical students. European Journal of Pharmaceutics and Biopharmaceutics in Melbourne. Prof. Dr. Christian Schlechtriem is Honorary Professor for Ecotoxi- Editorial Board: Prof. Dr. Jennifer Dressman Dr. Sheraz Gul is Adjunct Lecturer at the NUI Galway, College of cology at the University Siegen and holds lectures and courses at the ­Medicine, Nursing & Health Sciences, Ireland and was an invited in­ RWTH Aachen University. European Journal of Pharmaceutical Sciences struc­tor at “MSc (Toxicology) – Screening Molecular Libraries Module“. Editorial Board: Prof. Dr. Jennifer Dressman, Dr. Matthias Wacker Lecturing assignments Matthias Teigeler holds lectures on Ecotoxicology at the University Dr. Kerstin Hund-Rinke holds lectures in ecotoxicology at Hochschu- for Applied Sciences Bingen and the Technical University Braunschweig European Pharmaceutical Review, Russell Publishing Ltd. Editorial Board: Dr. Sheraz Gul Dr. Natasja de Bruin holds seminars at the Goethe University le Osnabrück (University of Applied Sciences). and is a lecturer for the Module Ecotoxicology, Advanced animal

­Hospital Frankfurt am Main and the Frankfurt International Research ­welfare training in fish toxicology, of “Berliner Fortbildungen“. Frontiers in Bioengineering and Biotechnology, School for Translational Biomedicine (FIRST). She participated in the Dr. Michael Klein holds lectures about modelling the environmental Frontiers Media S.A.; Workshop “Fraunhofer CIMD Young Scientist Program“ of Fraunhofer fate of chemicals at RWTH Aachen. Prof. Dr. Andreas Vilcinskas is Professor for Applied Entomology Associate Editor: Dr. Dr.-Ing. Johannes F. Buyel Cluster of Excellence for Immune-Mediated Diseases (CIMD). and Director of the established Institute for Insect Bio­technology, both Dr. Kwang-Zin Lee lectures at the Institute for Insect Biotechnology at the Justus Liebig University Gießen. Frontiers in Pharmacology, Frontiers Media S.A. Prof. Dr. Mark Bücking holds lectures at the Faculty of Mathe- in the field of Applied Entomology at the Justus Liebig University of Editorial Board: Prof. Dr. Dieter Steinhilber matics and Natural Sciences at the University of Wuppertal and is Gießen.

108 109 NETWORKS IN SCIENCE AND INDUSTRY

Frontiers in Plant Biotechnology, Frontiers Media S.A. Committees DAkkS, Deutsche Dutch NeuroFederation Fachbeirat zum Master- FPI e.V., Food-Processing Industrial Quality and Associate Editor: Prof. Dr. Dirk Prüfer Akkreditierungsstelle Dr. Natasja de Bruin studiengang »Boden, Initiative Productivity Centre (IQPC) Altmetric Fachbegutachter: ­Gewässer, Altlasten« an Mitglied des Vorstands: Pharmaceutical Advisory Board: Handbuch der Bodenuntersuchung, Wiley-VCH Ambassador: Dr. Kerstin Hund-Rinke ECHA/EFSA, Endocrine der Hochschule/ Universität Prof. Dr. Mark Bücking Dr. Sheraz Gul Beirat: Dr. Dieter Hennecke Dr. Sheraz Gul Disrupting Guidance Osnabrück DECHEMA Consultation Group Dr. Kerstin Hund-Rinke Fraunhofer Chile Research Initiative Gesundheitsindust- Integrated Environmental Assessment and Management, Wiley Artificial Intelligence Center Mitglied im Zukunftsforum: Hearing expert: Board of Directors rie Hessen Editorial Board: Dr. Udo Hommen Hamburg (ARIC) e.V. Dr. Dr.-Ing. Johannes F. Buyel Prof. Dr. Christoph Schäfers FBU, Fachbeirat Prof. Dr. Dirk Prüfer Mitglied des Lenkungskreises: Beirat: Bodenuntersuchungen Prof. Dr. Dr. Gerd Geißlinger Journal of Applied Ichthyology, Wiley-Blackwell Prof. Dr. Carsten Claussen DFG, Fachkollegium, Medizin, ECNP, European College of Dr. Dieter Hennecke Fraunhofer Cluster of Excel- Editorial Board: Prof. Dr. Christian Schlechtriem Sektion Entzündungsforschung Neuropsychopharmacology & lence Immune-Mediated International Atomic Energy Ausschuss für Innovation, Prof. Dr. Dr. Gerd Geißlinger Preclinical Data Forum Net- FENS Federation of European Diseases CIMD Agency (IAEA) Journal of Oil Palm Research, Malaysian Palm Oil Board Handelskammer Hamburg work Neuroscience Societies Sprecher: Wissenschaftlicher Berater: Editorial Board: Prof. Dr. Dirk Prüfer Prof. Dr. Carsten Claussen Deutschen Institut für Dr. Natasja de Bruin Dr. Natasja de Bruin Prof. Dr. Dr. Gerd Geißlinger Prof. Dr. Marc F. Schetelig Bautechnik, Projektgruppe Geschäftsführer: Journal of Pharmaceutical Sciences, Elsevier BMBF, KMU-innovativ: »Modellierung« EFSA Working Group Finanzkommission des PD Dr. Frank Behrens International Society for Stem Scientific Advisor: Prof. Dr. Matthias Wacker Biotechnologie – BioChance Dr. Michael Klein Developing an EFSA scientific Senats der WWU Münster Cell Research (ISSCR) Gutachterkreis: report for the FOCUS surface Mitglied Fraunhofer Strategie-Kommis- Mitglied des Internationalen Journal of Pharmacy and Pharmacology, Wiley Prof. Dr. Dieter Steinhilber DIN NA 119 Normenausschuss water repair action Prof. Dr. Dirk Prüfer sion Gesundheitsforschung Komitees: Associate Editor: Prof. Dr. Jennifer Dressman Wasserwesen (NAW): Dr. Michael Klein Leitung: Dr. Ole Pless Editorial Board: Prof. Dr. Matthias Wacker BMELV, Wissenschaftlicher - NA 119-01-02-05 UA FOCUS (Forum for internatio- Prof. Dr. Dr. Gerd Geißlinger Beirat für Düngungsfragen Elutionsverfahren EFSA Working Group on the nal coordination of pesticide ISO/TC 190 SC2, WG10 Soil Plant Cell Reports, Springer Stellvertretende Vorsitzende: Dr. Dieter Hennecke new guidance document fate models and their use), GDCh, Fachgruppe Umwelt- quality – Elaborating general Editorial Board: Prof. Dr. Stefan Schillberg Dr. Kerstin Hund-Rinke about persistence in soil Work Group »Version chemie und Ökotoxikologie: aspects of sampling - NA 119-01-02-02-01 AK Dr. Michael Klein Control« Karlheinz Weinfurtner PLoS ONE, Public Library of Science BVL, Expertengruppe zur Bioverfügbarkeit Dr. Michael Klein - Arbeitskreis Boden Editorial Board: Prof. Dr. Dieter Steinhilber Erstellung einer Richtlinie Dr. Kerstin Derz ETH Review Panel (Depart- Leitung: ISO/TC 190 SC7, für Fischfütterungsstudien ment of Chemistry and Forschungskommission des Dr. Dieter Hennecke WG4 Human exposure Scientific Report, Springer Nature Limited Prof. Dr. Christian Schlechtriem - NA 119-01-02-04 UA Applied Biosciences) Fachbereichs Medizin der Convenor: Editorial Board: PD Dr. Susanne Schiffmann Biologische Verfahren Prof. Dr. Jennifer Dressman Goethe Universität - Arbeitskreis Dr. Kerstin Derz Bundesinstitut für Dr. Kerstin Hund-Rinke Prof. Dr. Dr. Gerd Geißlinger Chemikalienbewertung Transgenic Research, Kluwer Academic Publishers Risikobewertung: EU COST Actions Dr. Martin Müller, Dr. Lena Kosak ISO/TC 190 SC7, Associate Editor: Prof. Dr. Stefan Schillberg Kommission für Kontaminan- - NA 119-01-02 AA CM 1406 and CA 15135 Gesellschaft für Versuchstier- WG6 Leaching tests ten und andere gesundheitlich Abfall und Bodenunter- German Management kunde, GV-SOLAS - Arbeitskreis Dr. Dieter Hennecke unerwünschte Stoffe in der suchung, UA 1 Probenahme Committee Matthias Teigeler Umweltmonitoring Lebensmittelkette Karlheinz Weinfurtner Substitute: Leitung: Kaertor Foundation, Prof. Dr. Mark Bücking Dr. Sheraz Gul Forschungsrat der Goethe- Dr. Heinz Rüdel Galicia Spain. - NA 119-01-02-06 UA Universität Expert Advisor for the Drug BVL, Expertengruppe zur Bodenschutz, Entsorgung, EU Cost Action Prof. Dr. Dr. Gerd Geißlinger Gesundheitsforschungs- Discovery portfolio: Erstellung einer Richtlinie Altlastensanierung, DNAqua-Net beauftragter der Dr. Philip Gribbon für Fischfütterungsstudien UA 2 Entsorgung Dr. Elke Eilebrecht Forum »Gesundheits- Fraunhofer-Gesellschaft Prof. Dr. Christian Schlechtriem Karlheinz Weinfurtner forschung« des BMBF Prof. Dr. Dr. Gerd Geißlinger Kommission zur Bewertung European Federation for Prof. Dr. Dr. Gerd Geißlinger wassergefährdender Stoffe Certara L.P. - NA 119-01-03-05-03 Pharmaceutical Sciences Hochschulforum der (KBwS) des BMU Scientific Advisory Board of AK Marine Biotests Vizepräsident: Food and Agricultural Hamburger Wirtschaft Prof. Dr. Christoph Schäfers Simcyp: Dr. Karsten Schlich Prof. Dr. Dieter Steinhilber Organization of the United Prof. Dr. Carsten Claussen Prof. Dr. Jennifer Dressman Nations Lenkungskreis LOEWE- DIN SPEC 92001 Künstliche Evaluation Panel for VIB Core Wissenschaftlicher Berater: House of Pharma and Zentrum TBG CZ-OPENSCREEN. Intelligenz – Qualitäts- facilities (Belgium) Prof. Dr. Marc F. Schetelig Healthcare Prof. Dr. Dr. Gerd Geißlinger Chair of Scientific Advisory anforderungen und Life Cycle Panel member for screening and Vorstandsmitglieder: Board: Management für KI Module imaging core facility review: Prof. Dr. Dr. Gerd Geißlinger, Dr. Philip Gribbon Dr. Sebastian Eilebrecht Dr. Philip Gribbon PD Dr. Frank Behrens

110 111 NETWORKS IN SCIENCE AND INDUSTRY

Malaysian Palm Oil Board Science Fund of the Republic Transcriptogen Ltd. Organization of Scientific Meetings and Courses (MPOB) of Serbia, Scientific Co-Founder: Programme Advisory Committee Project Peer Reviewer: Dr. Sheraz Gul (PAC) of the Malaysian Palm Oil Dr. Sheraz Gul 3rd Exzellence Course SPA Psoriasis-Arthritis and Axial Board: UBA, Arbeitskreis ­Spondyloarthritis Prof. Dr. Dirk Prüfer Senat der WWU Münster Fortentwicklung von Seeheim-Jugenheim, October 24 to 26, 2019, let by PD Dr. med. Frank Stellvertretendes Mitglied: Prüfmethoden im Behrens in cooperation with House of Pharma & Healthcare NORMAN – Network of Prof. Dr. Dirk Prüfer Rahmen des Stoffrechts, reference laboratories, AK Ökotoxikologie, ELRIG Discovery 2019, Looking back to Future research centres and related SETAC Europe Interest Group: Akkumulation und Abbau Liverpool, November 4 to 5, 2019, member of the scientific organisations for monitoring Effect Modeling in der Umwelt ­organization committee and session chair Dr. Philip Gribbon of emerging environmental Lenkungsausschuss: Prof. Dr. Christoph Schäfers substances: Dr. Udo Hommen Symposium: New opportunities for drug discovery with stem United States Pharmacopeial cell technologies - Working Group SETAC Global Interest Group: Convention: Expertengremi- Kobe, August 29, 2019, organized in cooperation with FBRI »Prioritization of emerging Bioaccumulation Science um für Neuentwicklungen im ­(foundation for Biomedical Research and Innovation, Kobe, Japan), substances« Ko-Vorsitz: Bereich der In vitro Assays Prof. Dr. Carsten Claussen Dr. Heinz Rüdel Prof. Dr. Christian Schlechtriem Prof. Dr. Matthias Wacker Immunology Day 2019 - Working Group SETAC Global Interest Group VDI/VDE »Datenmanagement Frankfurt am Main, June 19, 2019, organized by the Fraunhofer »Bioassays and biomarkers in Lenkungsausschuss: im Bereich Life Sciences« ­Cluster of Excellence for Immune-Mediated Diseases CIMD water quality monitoring« Dr. Udo Hommen VDI 6320 Dr. Elke Eilebrecht Vizevorsitzender: Workshop »4th MuTaLig COST Action Training School, CA Society for Laboratory Auto- Dr. Manfred Kohler 15135« OECD Expert Group on Fish mation and Screening Hamburg, March 6 to 8, 2019, organized by the MuTaLig COST Bioaccumulation Elected fellow and member of VIB Screening Core, Belgium ­Action Committee and Fraunhofer IME, Dr. Sheraz Gul Prof. Dr. Christian Schlechtriem the »Advocacy Committee«: Advisory Board Member: Dr. Philip Gribbon Dr. Sheraz Gul Workshop: C-CNS Drug Discovery OECD Fish Drafting Group Kobe, July 11, 2019, organized in cooperation with FBRI ­(foundation Matthias Teigeler, Society for Laboratory Auto- World Health Organization for Biomedical Research and Innovation, Kobe, Japan), Dr. Sheraz Gul Prof. Dr. Christoph Schäfers mation and Screening (WHO), Vector Control Member of the Strategic Advisory Group (VCAG): Workshop »Current State and Future Expectations of Translatio- OECD Validation Management Relations Council: Prof. Dr. Marc F. Schetelig nal Modeling Strategies to Support Drug Product Development, Group on Ecotoxicity Testing Dr. Sheraz Gul Manufacturing Changes and Controls« (VMG-eco) Maryland, USA, September 23 to 26, 2019, organized by FDA, Invited national experts: Stiftung für Unternehmens- ­co-organizer Prof. Dr. Jennifer Dressman Matthias Teigeler recht an der Heinrich Heine Prof. Dr. Christoph Schäfers Universität Düsseldorf Workshop: Drug Discovery and Development Kuratoriumsmitglied: Hamburg, 17. bis 18. Oktober 2019, organized in cooperation with OECD Working Party on Prof. Dr. Carsten Claussen cisbio, Dr. Sheraz Gul Manufactured Nanomaterials (WPMN) Stiftungsrat der Dr. Robert Workshop: From Molecule to Medicine Dr. Kerstin Hund-Rinke Pfleger Stiftung Ljubljana, March 18 to 20, 2019, Epichembio COST Action Training Prof. Dr. Dr. Gerd Geißlinger School, CM 1406, Dr. Sheraz Gul Pharmadialog der Bundesre- gierung Stiftungsrat der Workshop »Nachwuchsförderung des Fraunhofer CIMD« Mitglied: Freundlich-Stiftung Frankfurt am Main, June 17 to 18, 2019, organized by the Fraunhofer­ Prof. Dr. Dr. Gerd Geißlinger Prof. Dr. Dr. Gerd Geißlinger Cluster of Excellence for Immune-Mediated Diseases CIMD

Research Data Alliance, GEDE Stiftung Westfälische - Group of European Data ­Wilhelms-Universität Münster Experts in RDA: Kuratorium: Dr. Manfred Kohler Prof. Dr. Dirk Prüfer

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Photo Acknowledgements Schetelig 68 l. Fraunhofer IME | Johannes Published by 46 Shutterstock | Dominique Buyel Fraunhofer Institute for Molecular Biology Cover Shutterstock | Vikks 68 r. Verband Schweizer Pilzpro- Landau and Applied Ecology IME 6 Shutterstock | The Hornbills 47 Fraunhofer IME | Birgit Orthen duzenten | Fritz Burkhalter Studio 48 Shutterstock | Anton Khrupin 69 l. DGRh | Thomas Hauss Forckenbeckstr. 6 8 Deutsches Museum, München 69 r. Fraunhofer IME | Andreas 50 Fraunhofer IME | Lena Grund- 52074 Aachen 9 Deutsches Museum, München mann Schütte 10 Fraunhofer IME | Birgit Orthen 51 l. Fraunhofer IME | Bernhard 70 l. Panthermedia | Haverpino Germany 15 l. Fraunhofer IME | Sebastian Blob 70 r. Fraunhofer IME | Ole Pless de Vries 71 l. Continental Reifen Deutsch- 51 M. Fraunhofer IME | Birgit All rights reserved. Reproduction only with 15 M. Birgit Orthen Orthen land GmbH 15 r. Fraunhofer IME | Stephan 51 r. Fraunhofer IME | Bernhard 71 r. Fraunhofer IME | Olga Arne permission from Fraunhofer IME. Hellwig Blob 72 r. Fraunhofer IME | Piotr 16 l. Fraunhofer IME | Frank 52 Fraunhofer IME | Christiane Banczerowski Peinemann Fischer 73 l. Fraunhofer IME | Birgit Editors 16 r. iStockfoto | Carlos 53 Fraunhofer IME | Christiane Orthen Prof. Dr. Dr. Gerd Geißlinger ­Gawronski 73 r. Fraunhofer IME | Ole Pless Fischer Prof. Dr. Christoph Schäfers 17 l. Shutterstock | makspogonii 54 Shutterstock | Anton Khrupin 74 Shutterstock | Anton Khrupin 17 M. Fraunhofer IME | Henrike 56 Fraunhofer IME | Benjamin 76 Shutterstock | Igor Shi Prof. Dr. Stefan Schillberg Schmidtberg Gengenbach 79 Shutterstock | JPC-PROD 17 r. Hessen schafft Wissen 57 l. Fraunhofer IME | Tilo Knape 91 Fraunhofer IME | Bernd Müller 18 Fraunhofer IME | Bernd Müller 57 M. Fraunhofer IME | Tilo 98 Shutterstock | Anton Khrupin Coordination 19 l. Fraunhofer IME | Nadja Knape 100 Fraunhofer IME | Birgit PR Team Fraunhofer IME Tafferner 57 r. Fraunhofer IME | Tilo Knape Orthen 19 M. Fraunhofer IME | Bernd 58 Fraunhofer IME | Tassilo Wol- 102 Shutterstock | Anton Müller lenweber ­Khrupin Concept and Design 19 r. Fraunhofer IME | Bernd 106 Shutterstock | Anton 59 Fraunhofer IME | Désirée PR Team Aachen Müller Schulz ­Khrupin 24 Fraunhofer IME | Bernd Müller 60 l. Fraunhofer IME | Björn 28 Shutterstock | Anton Khrupin Windshügel Reporting Period 31 Panthermedia | jahina 60 r. Fraunhofer IME | Björn January 1 until December 31, 2019 33 l. Fraunhofer IME | Birgit Windshügel Orthen 61 Klaus-Peter Kappest | 33 r. Jost Muth Klaus-Peter Kappest © Fraunhofer IME 35 l. Fraunhofer IME | Christoph 62 Shutterstock | Vladyslav Emmerich Severyn Aachen, Münster, Schmallenberg, 35 r. Michael Parnham | Michael 64 l. Fraunhofer IME | Ronald Gießen, Frankfurt am Main and Hamburg Parnham Jäpel 37 l. Fraunhofer IME | Tim 64 r. Fraunhofer CIMD | Jürgen Lüddecke Lecher 37 r. Fraunhofer IME | Birgit 65 l. Hessen schafft Wissen Orthen 65 r Fraunhofer IME | Jonas 39 r. MEV Verlag GmbH, Glawe ­Germany | Joachim Rapp 66 l. Fraunhofer IME | Hendrich 39 l. ThyssenKrupp Steel AG Quitmann 40 Fraunhofer IME | Sheraz Gul 66 r. Senatskanzlei Freie und 41 o. Fraunhofer IME | Laura Hansestadt Hamburg | Jan-Niklas Chachulski Pries 41 u. Fraunhofer IME | Sheraz 67 l. Cusanus-Gymnasium Er- Gul kelenz | Viethen 42 Shutterstock | Anton Khrupin 67 r. Fraunhofer IME | Kathrin 45 Fraunhofer IME | Marc Schneider

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